128 lines
205 KiB
Text
128 lines
205 KiB
Text
<!DOCTYPE html>
|
|
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" class="no-js no-jr">
|
|
<head>
|
|
<!-- For pinger, set start time and add meta elements. -->
|
|
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
|
|
|
<!-- Logger begin -->
|
|
<meta name="ncbi_db" content="books">
|
|
<meta name="ncbi_pdid" content="book-part">
|
|
<meta name="ncbi_acc" content="NBK55068">
|
|
<meta name="ncbi_domain" content="mlprobe">
|
|
<meta name="ncbi_report" content="reader">
|
|
<meta name="ncbi_type" content="fulltext">
|
|
<meta name="ncbi_objectid" content="">
|
|
<meta name="ncbi_pcid" content="/NBK55068/?report=reader">
|
|
<meta name="ncbi_pagename" content="Antagonists of IAP-family anti-apoptotic proteins - Probe 2 - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf">
|
|
<meta name="ncbi_bookparttype" content="chapter">
|
|
<meta name="ncbi_app" content="bookshelf">
|
|
<!-- Logger end -->
|
|
|
|
<!--component id="Page" label="meta"/-->
|
|
<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Antagonists of IAP-family anti-apoptotic proteins - Probe 2 - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
|
|
<meta charset="utf-8">
|
|
<meta name="apple-mobile-web-app-capable" content="no">
|
|
<meta name="viewport" content="initial-scale=1,minimum-scale=1,maximum-scale=1,user-scalable=no">
|
|
<meta name="jr-col-layout" content="auto">
|
|
<meta name="jr-prev-unit" content="/books/n/mlprobe/ml200/?report=reader">
|
|
<meta name="jr-next-unit" content="/books/n/mlprobe/ml170/?report=reader">
|
|
<meta name="bk-toc-url" content="/books/n/mlprobe/?report=toc">
|
|
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE">
|
|
<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
|
|
<meta name="citation_title" content="Antagonists of IAP-family anti-apoptotic proteins - Probe 2">
|
|
<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
|
|
<meta name="citation_date" content="2011/02/10">
|
|
<meta name="citation_author" content="Marcos Lopez">
|
|
<meta name="citation_author" content="Kate Welsh">
|
|
<meta name="citation_author" content="Hongbin Yuan">
|
|
<meta name="citation_author" content="Derek Stonich">
|
|
<meta name="citation_author" content="Ying Su">
|
|
<meta name="citation_author" content="Xochella Garcia">
|
|
<meta name="citation_author" content="Michael Cuddy">
|
|
<meta name="citation_author" content="Richard Houghten">
|
|
<meta name="citation_author" content="Eduard Sergienko">
|
|
<meta name="citation_author" content="John C Reed">
|
|
<meta name="citation_author" content="Robert Ardecky">
|
|
<meta name="citation_author" content="Santhi Reddy">
|
|
<meta name="citation_author" content="Darren Finlay">
|
|
<meta name="citation_author" content="Kristiina Vuori">
|
|
<meta name="citation_author" content="Shakeela Dad">
|
|
<meta name="citation_author" content="Thomas DY Chung">
|
|
<meta name="citation_author" content="Nicholas DP Cosford">
|
|
<meta name="citation_pmid" content="21634080">
|
|
<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK55068/">
|
|
<link rel="schema.DC" href="http://purl.org/DC/elements/1.0/">
|
|
<meta name="DC.Title" content="Antagonists of IAP-family anti-apoptotic proteins - Probe 2">
|
|
<meta name="DC.Type" content="Text">
|
|
<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
|
|
<meta name="DC.Contributor" content="Marcos Lopez">
|
|
<meta name="DC.Contributor" content="Kate Welsh">
|
|
<meta name="DC.Contributor" content="Hongbin Yuan">
|
|
<meta name="DC.Contributor" content="Derek Stonich">
|
|
<meta name="DC.Contributor" content="Ying Su">
|
|
<meta name="DC.Contributor" content="Xochella Garcia">
|
|
<meta name="DC.Contributor" content="Michael Cuddy">
|
|
<meta name="DC.Contributor" content="Richard Houghten">
|
|
<meta name="DC.Contributor" content="Eduard Sergienko">
|
|
<meta name="DC.Contributor" content="John C Reed">
|
|
<meta name="DC.Contributor" content="Robert Ardecky">
|
|
<meta name="DC.Contributor" content="Santhi Reddy">
|
|
<meta name="DC.Contributor" content="Darren Finlay">
|
|
<meta name="DC.Contributor" content="Kristiina Vuori">
|
|
<meta name="DC.Contributor" content="Shakeela Dad">
|
|
<meta name="DC.Contributor" content="Thomas DY Chung">
|
|
<meta name="DC.Contributor" content="Nicholas DP Cosford">
|
|
<meta name="DC.Date" content="2011/02/10">
|
|
<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK55068/">
|
|
<meta name="description" content="Various Inhibitors of Apoptosis Proteins (IAPs) are over-expressed in specific types of cancer, and some tumors over-express more than one member of this family of proteins simultaneously. Given that multiple IAPs are simultaneously over-expressed in many cancers, unfortunately antisense or RNA interference (RNAi) methods for assessing function of these proteins are presently often lacking. Therefore, probing the competition of small molecule compounds against either the BIR2 or BIR3 SMAC-binding sites on IAPs, such as XIAP, cIAP1, cIAP2 or other IAPs from human and other organisms will serve as useful tools for elucidating their roles in cancer biology. In this study, we investigated small molecule compounds that selectively mimic the effects of SMAC (second mitochondria-derived activator of caspase) in antagonizing IAPs by causing them to release Caspases. These non-peptidyl chemical inhibitors would have advantages over SMAC peptides, in terms of their greater cell permeability, stability, and in vivo pharmacology. As such, the probe identified in this report ML183 (CID 44176340) met the project’s goal of displaying potent binding affinity and selectivity for the BIR2 domain of XIAP. Moreover, in that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a potent inducer of apoptosis in a wide variety of tumor cells, another valuable finding of this project is that it also promotes cell survival against a challenge by rhTRAIL, an inducer of cell death.">
|
|
<meta name="og:title" content="Antagonists of IAP-family anti-apoptotic proteins - Probe 2">
|
|
<meta name="og:type" content="book">
|
|
<meta name="og:description" content="Various Inhibitors of Apoptosis Proteins (IAPs) are over-expressed in specific types of cancer, and some tumors over-express more than one member of this family of proteins simultaneously. Given that multiple IAPs are simultaneously over-expressed in many cancers, unfortunately antisense or RNA interference (RNAi) methods for assessing function of these proteins are presently often lacking. Therefore, probing the competition of small molecule compounds against either the BIR2 or BIR3 SMAC-binding sites on IAPs, such as XIAP, cIAP1, cIAP2 or other IAPs from human and other organisms will serve as useful tools for elucidating their roles in cancer biology. In this study, we investigated small molecule compounds that selectively mimic the effects of SMAC (second mitochondria-derived activator of caspase) in antagonizing IAPs by causing them to release Caspases. These non-peptidyl chemical inhibitors would have advantages over SMAC peptides, in terms of their greater cell permeability, stability, and in vivo pharmacology. As such, the probe identified in this report ML183 (CID 44176340) met the project’s goal of displaying potent binding affinity and selectivity for the BIR2 domain of XIAP. Moreover, in that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a potent inducer of apoptosis in a wide variety of tumor cells, another valuable finding of this project is that it also promotes cell survival against a challenge by rhTRAIL, an inducer of cell death.">
|
|
<meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK55068/">
|
|
<meta name="og:site_name" content="NCBI Bookshelf">
|
|
<meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png">
|
|
<meta name="twitter:card" content="summary">
|
|
<meta name="twitter:site" content="@ncbibooks">
|
|
<meta name="bk-non-canon-loc" content="/books/n/mlprobe/ml183/?report=reader">
|
|
<link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK55068/">
|
|
<link href="https://fonts.googleapis.com/css?family=Archivo+Narrow:400,700,400italic,700italic&subset=latin" rel="stylesheet" type="text/css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/libs.min.css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/jr.min.css">
|
|
<meta name="format-detection" content="telephone=no">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css//books_print.min.css" type="text/css" media="print">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_reader.min.css" type="text/css">
|
|
<style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style>
|
|
|
|
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico">
|
|
<meta name="ncbi_phid" content="CE8E232D7D65F9310000000000DE00C7.m_5">
|
|
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3849091.css"></head>
|
|
<body>
|
|
<!-- Book content! -->
|
|
|
|
|
|
<div id="jr" data-jr-path="/corehtml/pmc/jatsreader/ptpmc_3.22/"><div class="jr-unsupported"><table class="modal"><tr><td><span class="attn inline-block"></span><br />Your browser does not support the NLM PubReader view.<br />Go to <a href="/pmc/about/pr-browsers/">this page</a> to see a list of supported browsers<br />or return to the <br /><a href="/books/NBK55068/?report=classic">regular view</a>.</td></tr></table></div><div id="jr-ui" class="hidden"><nav id="jr-head"><div class="flexh tb"><div id="jr-tb1"><a id="jr-links-sw" class="hidden" title="Links"><svg xmlns="http://www.w3.org/2000/svg" version="1.1" x="0px" y="0px" viewBox="0 0 70.6 85.3" style="enable-background:new 0 0 70.6 85.3;vertical-align:middle" xml:space="preserve" width="24" height="24">
|
|
<style type="text/css">.st0{fill:#939598;}</style>
|
|
<g>
|
|
<path class="st0" d="M36,0C12.8,2.2-22.4,14.6,19.6,32.5C40.7,41.4-30.6,14,35.9,9.8"></path>
|
|
<path class="st0" d="M34.5,85.3c23.2-2.2,58.4-14.6,16.4-32.5c-21.1-8.9,50.2,18.5-16.3,22.7"></path>
|
|
<path class="st0" d="M34.7,37.1c66.5-4.2-4.8-31.6,16.3-22.7c42.1,17.9,6.9,30.3-16.4,32.5h1.7c-66.2,4.4,4.8,31.6-16.3,22.7 c-42.1-17.9-6.9-30.3,16.4-32.5"></path>
|
|
</g>
|
|
</svg> Books</a></div><div class="jr-rhead f1 flexh"><div class="head"><a href="/books/n/mlprobe/ml200/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="body"><div class="t">Antagonists of IAP-family anti-apoptotic proteins - Probe 2</div><div class="j">Probe Reports from the NIH Molecular Libraries Program [Internet]</div></div><div class="tail"><a href="/books/n/mlprobe/ml170/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></div><div id="jr-tb2"><a id="jr-bkhelp-sw" class="btn wsprkl hidden" title="Help with NLM PubReader">?</a><a id="jr-help-sw" class="btn wsprkl hidden" title="Settings and typography in NLM PubReader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512" preserveAspectRatio="none"><path d="M462,283.742v-55.485l-29.981-10.662c-11.431-4.065-20.628-12.794-25.274-24.001 c-0.002-0.004-0.004-0.009-0.006-0.013c-4.659-11.235-4.333-23.918,0.889-34.903l13.653-28.724l-39.234-39.234l-28.72,13.652 c-10.979,5.219-23.68,5.546-34.908,0.889c-0.005-0.002-0.01-0.003-0.014-0.005c-11.215-4.65-19.933-13.834-24-25.273L283.741,50 h-55.484l-10.662,29.981c-4.065,11.431-12.794,20.627-24.001,25.274c-0.005,0.002-0.009,0.004-0.014,0.005 c-11.235,4.66-23.919,4.333-34.905-0.889l-28.723-13.653l-39.234,39.234l13.653,28.721c5.219,10.979,5.545,23.681,0.889,34.91 c-0.002,0.004-0.004,0.009-0.006,0.013c-4.649,11.214-13.834,19.931-25.271,23.998L50,228.257v55.485l29.98,10.661 c11.431,4.065,20.627,12.794,25.274,24c0.002,0.005,0.003,0.01,0.005,0.014c4.66,11.236,4.334,23.921-0.888,34.906l-13.654,28.723 l39.234,39.234l28.721-13.652c10.979-5.219,23.681-5.546,34.909-0.889c0.005,0.002,0.01,0.004,0.014,0.006 c11.214,4.649,19.93,13.833,23.998,25.271L228.257,462h55.484l10.595-29.79c4.103-11.538,12.908-20.824,24.216-25.525 c0.005-0.002,0.009-0.004,0.014-0.006c11.127-4.628,23.694-4.311,34.578,0.863l28.902,13.738l39.234-39.234l-13.66-28.737 c-5.214-10.969-5.539-23.659-0.886-34.877c0.002-0.005,0.004-0.009,0.006-0.014c4.654-11.225,13.848-19.949,25.297-24.021 L462,283.742z M256,331.546c-41.724,0-75.548-33.823-75.548-75.546s33.824-75.547,75.548-75.547 c41.723,0,75.546,33.824,75.546,75.547S297.723,331.546,256,331.546z"></path></svg></a><a id="jr-fip-sw" class="btn wsprkl hidden" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-rtoc-sw" class="btn wsprkl hidden" title="Table of Contents"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,20h10v8H20V20zM36,20h44v8H36V20zM20,37.33h10v8H20V37.33zM36,37.33h44v8H36V37.33zM20,54.66h10v8H20V54.66zM36,54.66h44v8H36V54.66zM20,72h10v8 H20V72zM36,72h44v8H36V72z"></path></svg></a></div></div></nav><nav id="jr-dash" class="noselect"><nav id="jr-dash" class="noselect"><div id="jr-pi" class="hidden"><a id="jr-pi-prev" class="hidden" title="Previous page"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a><div class="pginfo">Page <i class="jr-pg-pn">0</i> of <i class="jr-pg-lp">0</i></div><a id="jr-pi-next" class="hidden" title="Next page"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div><div id="jr-is-tb"><a id="jr-is-sw" class="btn wsprkl hidden" title="Switch between Figures/Tables strip and Progress bar"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><rect x="10" y="40" width="20" height="20"></rect><rect x="40" y="40" width="20" height="20"></rect><rect x="70" y="40" width="20" height="20"></rect></svg></a></div><nav id="jr-istrip" class="istrip hidden"><a id="jr-is-prev" href="#" class="hidden" title="Previous"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M80,40 60,65 80,90 70,90 50,65 70,40z M50,40 30,65 50,90 40,90 20,65 40,40z"></path><text x="35" y="25" textLength="60" style="font-size:25px">Prev</text></svg></a><a id="jr-is-next" href="#" class="hidden" title="Next"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,40 40,65 20,90 30,90 50,65 30,40z M50,40 70,65 50,90 60,90 80,65 60,40z"></path><text x="15" y="25" textLength="60" style="font-size:25px">Next</text></svg></a></nav><nav id="jr-progress"></nav></nav></nav><aside id="jr-links-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">NCBI Bookshelf</div></div><div class="cnt lol f1"><a href="/books/">Home</a><a href="/books/browse/">Browse All Titles</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://www.facebook.com/sharer/sharer.php?u=https://www.ncbi.nlm.nih.gov/books/NBK55068/"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24" preserveAspectRatio="none"><g><path d="M 17.996,32L 12,32 L 12,16 l-4,0 l0-5.514 l 4-0.002l-0.006-3.248C 11.993,2.737, 13.213,0, 18.512,0l 4.412,0 l0,5.515 l-2.757,0 c-2.063,0-2.163,0.77-2.163,2.209l-0.008,2.76l 4.959,0 l-0.585,5.514L 18,16L 17.996,32z"></path></g></svg> Share on Facebook</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://twitter.com/intent/tweet?url=https://www.ncbi.nlm.nih.gov/books/NBK55068/&text=Antagonists%20of%20IAP-family%20anti-apoptotic%20proteins%20-%20Probe%202"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24"><g><path d="M 32,6.076c-1.177,0.522-2.443,0.875-3.771,1.034c 1.355-0.813, 2.396-2.099, 2.887-3.632 c-1.269,0.752-2.674,1.299-4.169,1.593c-1.198-1.276-2.904-2.073-4.792-2.073c-3.626,0-6.565,2.939-6.565,6.565 c0,0.515, 0.058,1.016, 0.17,1.496c-5.456-0.274-10.294-2.888-13.532-6.86c-0.565,0.97-0.889,2.097-0.889,3.301 c0,2.278, 1.159,4.287, 2.921,5.465c-1.076-0.034-2.088-0.329-2.974-0.821c-0.001,0.027-0.001,0.055-0.001,0.083 c0,3.181, 2.263,5.834, 5.266,6.438c-0.551,0.15-1.131,0.23-1.73,0.23c-0.423,0-0.834-0.041-1.235-0.118 c 0.836,2.608, 3.26,4.506, 6.133,4.559c-2.247,1.761-5.078,2.81-8.154,2.81c-0.53,0-1.052-0.031-1.566-0.092 c 2.905,1.863, 6.356,2.95, 10.064,2.95c 12.076,0, 18.679-10.004, 18.679-18.68c0-0.285-0.006-0.568-0.019-0.849 C 30.007,8.548, 31.12,7.392, 32,6.076z"></path></g></svg> Share on Twitter</a></div></aside><aside id="jr-rtoc-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Table of Content</div></div><div class="cnt lol f1"><a href="/books/n/mlprobe/?report=reader">Title Information</a><a href="/books/n/mlprobe/toc/?report=reader">Table of Contents Page</a></div></aside><aside id="jr-help-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Settings</div></div><div class="cnt f1"><div id="jr-typo-p" class="typo"><div><a class="sf btn wsprkl">A-</a><a class="lf btn wsprkl">A+</a></div><div><a class="bcol-auto btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 200 100" preserveAspectRatio="none"><text x="10" y="70" style="font-size:60px;font-family: Trebuchet MS, ArialMT, Arial, sans-serif" textLength="180">AUTO</text></svg></a><a class="bcol-1 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M15,25 85,25zM15,40 85,40zM15,55 85,55zM15,70 85,70z"></path></svg></a><a class="bcol-2 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M5,25 45,25z M55,25 95,25zM5,40 45,40z M55,40 95,40zM5,55 45,55z M55,55 95,55zM5,70 45,70z M55,70 95,70z"></path></svg></a></div></div><div class="lol"><a class="" href="/books/NBK55068/?report=classic">Switch to classic view</a><a href="/books/NBK55068/pdf/Bookshelf_NBK55068.pdf">PDF (1.3M)</a><a href="/books/NBK55068/?report=printable">Print View</a></div></div></aside><aside id="jr-bkhelp-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Help</div></div><div class="cnt f1 lol"><a id="jr-helpobj-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/help.xml" href="">Help</a><a href="mailto:info@ncbi.nlm.nih.gov?subject=PubReader%20feedback%20%2F%20NBK55068%20%2F%20sid%3ACE8B5AF87C7FFCB1_0191SID%20%2F%20phid%3ACE8E232D7D65F9310000000000DE00C7.4">Send us feedback</a><a id="jr-about-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/about.xml" href="">About PubReader</a></div></aside><aside id="jr-objectbox" class="thidden hidden"><div class="jr-objectbox-close wsprkl">✘</div><div class="jr-objectbox-inner cnt"><div class="jr-objectbox-drawer"></div></div></aside><nav id="jr-pm-left" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Previous Page</text></svg></nav><nav id="jr-pm-right" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Next Page</text></svg></nav><nav id="jr-fip" class="hidden"><nav id="jr-fip-term-p"><input type="search" placeholder="search this page" id="jr-fip-term" autocorrect="off" autocomplete="off" /><a id="jr-fip-mg" class="wsprkl btn" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK55068_"><span class="title" itemprop="name">Antagonists of IAP-family anti-apoptotic proteins - Probe 2</span></h1><p class="contribs">Lopez M, Welsh K, Yuan H, et al.</p><p class="fm-aai"><a href="#_NBK55068_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Various Inhibitors of Apoptosis Proteins (IAPs) are over-expressed in specific types of cancer, and some tumors over-express more than one member of this family of proteins simultaneously. Given that multiple IAPs are simultaneously over-expressed in many cancers, unfortunately antisense or RNA interference (RNAi) methods for assessing function of these proteins are presently often lacking. Therefore, probing the competition of small molecule compounds against either the BIR2 or BIR3 SMAC-binding sites on IAPs, such as XIAP, cIAP1, cIAP2 or other IAPs from human and other organisms will serve as useful tools for elucidating their roles in cancer biology. In this study, we investigated small molecule compounds that selectively mimic the effects of SMAC (second mitochondria-derived activator of caspase) in antagonizing IAPs by causing them to release Caspases. These non-peptidyl chemical inhibitors would have advantages over SMAC peptides, in terms of their greater cell permeability, stability, and in vivo pharmacology. As such, the probe identified in this report <a href="/pcsubstance/?term=ML183[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML183</a> (CID 44176340) met the project’s goal of displaying potent binding affinity and selectivity for the BIR2 domain of XIAP. Moreover, in that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a potent inducer of apoptosis in a wide variety of tumor cells, another valuable finding of this project is that it also promotes cell survival against a challenge by rhTRAIL, an inducer of cell death.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> R03 MH081277-01</p><p><b>Screening Center Name & PI</b>: Sanford-Burnham Center for Chemical Genomics & Dr John C Reed</p><p><b>Chemistry Center Name & PI:</b> Sanford-Burnham Center for Chemical Genomics & Dr John C Reed</p><p><b>Assay Submitter & Institution:</b> Dr John C Reed & Burnham Institute for Medical Research</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1638" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1638</a></p><div id="ml183.s1"><h2 id="_ml183_s1_">Probe Structure & Characteristics</h2><p>(This report describes a 2<sup>nd</sup> probe for XIAP elucidating another structurally distinct chemical scaffold with improved potency and selectivity for the BIR1/2 domain over the BIR3 domain of XIAP compared to the 1<sup>st</sup> probe CID 25241665, submitted in May of 2009)</p><div id="ml183.fu1" class="figure"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu1.jpg" alt="Image ml183fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml183tu1"><a href="/books/NBK55068/table/ml183.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml183tu1" rid-ob="figobml183tu1"><img class="small-thumb" src="/books/NBK55068/table/ml183.tu1/?report=thumb" src-large="/books/NBK55068/table/ml183.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml183.tu1"><a href="/books/NBK55068/table/ml183.tu1/?report=objectonly" target="object" rid-ob="figobml183tu1">Table</a></h4></div></div></div><div id="ml183.s2"><h2 id="_ml183_s2_">Recommendations for the scientific use of this probe</h2><p>Various IAP-family proteins are over-expressed in specific types of cancer and some tumors over-express more than one member of the family simultaneously. Given that multiple IAPs are simultaneously over-expressed in many cancers, antisense or RNA interference (RNAi) methods for assessing function of these proteins are often lacking. Therefore, probing the competition of small molecule compounds against either the BIR2 or BIR3 SMAC-binding sites on Inhibitor of Apoptosis Protein (IAP) such as XIAP, cIAP1, cIAP2 or other IAPs from human and other organisms will serve as useful tools for elucidating their roles in cancer biology.</p></div><div id="ml183.s3"><h2 id="_ml183_s3_">1. Scientific Rationale for Project</h2><div id="ml183.s4"><h3>Specific aims</h3><p>The goal of this project was to generate small molecule compounds that mimic the effects of SMAC peptides, inhibiting the function of Inhibitor of Apoptosis Proteins (IAPs).</p></div><div id="ml183.s5"><h3>Background and Significance</h3><p>Apoptosis, or programmed cell death, is a critical cellular process in normal development and homeostasis of multicellular organisms (<a class="bibr" href="#ml183.r1" rid="ml183.r1">1</a>). Caspases are the executioners in both intrinsic and extrinsic pathways of apoptosis by cleaving a plethora of cellular components (<a class="bibr" href="#ml183.r2" rid="ml183.r2">2</a>). These intracellular proteases are suppressed by Inhibitor of Apoptosis Proteins (IAPs), a family of evolutionarily conserved anti-apoptotic proteins (<a class="bibr" href="#ml183.r3" rid="ml183.r3">3</a>). The X-linked inhibitor of apoptosis, XIAP, is a key member of the family of intrinsic inhibitors of apoptosis proteins (IAP), which block cell death both <i>in vitro</i> and <i>in vivo</i> by virtue of inhibition of two effector caspases (caspase-3 and -7) and an initiator caspase (caspase-9). XIAP contains three baculoviral IAP repeat (BIR) domains, defined by a novel ~80 amino acid motif. The third domain (BIR3) of XIAP selectively binds to the amino terminus of the caspase-9 linker peptide while the BIR2 domain inhibits both caspase-3 and caspase-7. This inhibiting activity of XIAP is negatively regulated by at least two XIAP interacting proteins, XAF1 and SMAC/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with low pl). As a dimer, SMAC targets both the BIR2 and BIR3 domains of XIAP. Proteins released from mitochondria (SMAC and HtrA2) (<a class="bibr" href="#ml183.r4" rid="ml183.r4 ml183.r5 ml183.r6">4–6</a>) can competitively displace IAPs from the Caspases, thus helping to drive apoptosis. It has been shown that only a few residues at the N-terminus of activated SMAC protein (4′mer) are sufficient to affect the release of IAPs from Caspases (<a class="bibr" href="#ml183.r7" rid="ml183.r7">7</a>).</p><p>In this study we investigated small molecule compounds that mimicked the effect of SMAC in antagonizing IAPs by causing them to release Caspases. Non-peptidyl chemical inhibitors would have advantages over SMAC peptides, in terms of cell permeability, stability, and <i>in vivo</i> pharmacology. Several strategies were employed for the design of small-molecular inhibitors of XIAP, including the structure-based rational design and synthesis of small molecules that mimic the binding interactions between this protein and SMAC.</p></div></div><div id="ml183.s6"><h2 id="_ml183_s6_">2. Project Description</h2><div id="ml183.s7"><h3>a. The original goal for probe characteristics</h3><p>All current probes are polypeptides derived from natural IAP inhibitors (e.g. SMAC or HtrA2), with the 4-mer being the smallest that can displace IAPs from caspases. This project looked for non-peptidyl small molecule chemical inhibitors that would have advantages over SMAC peptides, in terms of cell permeability, stability, <i>in vivo</i> pharmacology and ideally having potency of 1 μM or better. In particular, the goal was to identify compounds that inhibit the BIR2 domain of XIAP, either selectively or in addition to inhibiting the BIR3 domain.</p></div><div id="ml183.s8"><h3>b. Assay implementation and screening</h3><div id="ml183.s9"><h4>i. PubChem Bioassay Name(s), AID(s), Assay-Type (Primary, DR, Counterscreen, Secondary)</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml183t1"><a href="/books/NBK55068/table/ml183.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml183t1" rid-ob="figobml183t1"><img class="small-thumb" src="/books/NBK55068/table/ml183.t1/?report=thumb" src-large="/books/NBK55068/table/ml183.t1/?report=previmg" alt="Table 1. PubChem Assay Summaries for Probe project." /></a><div class="icnblk_cntnt"><h4 id="ml183.t1"><a href="/books/NBK55068/table/ml183.t1/?report=objectonly" target="object" rid-ob="figobml183t1">Table 1</a></h4><p class="float-caption no_bottom_margin">PubChem Assay Summaries for Probe project. </p></div></div></div><div id="ml183.s10"><h4>ii. Assay Rationale & Description</h4><p>This XIAP dose response assay was developed and performed to confirm hits originally identified in the XIAP HTS binding assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1018" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1018</a>) and to study the structure-activity relationship of analogues of the confirmed hits. Compounds were acquired from commercial sources or synthesized in-house.</p><p>The rationale for the assay was based on the disruption of fluorescence polarization resulting from binding of a his-tagged-BIR1-BIR2 (baculoviral IAP repeat, “Bir1/2”) domain protein derived from two of the three conserved caspase binding “BIR” domains of XIAP to a rhodamine tagged 7-mer N-terminal SMAC peptide.</p><div id="ml183.s11"><h5>Assay materials</h5><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml183t2"><a href="/books/NBK55068/table/ml183.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml183t2" rid-ob="figobml183t2"><img class="small-thumb" src="/books/NBK55068/table/ml183.t2/?report=thumb" src-large="/books/NBK55068/table/ml183.t2/?report=previmg" alt="Table 2. Reagents used for the uHTS experiments." /></a><div class="icnblk_cntnt"><h4 id="ml183.t2"><a href="/books/NBK55068/table/ml183.t2/?report=objectonly" target="object" rid-ob="figobml183t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Reagents used for the uHTS experiments. </p></div></div><div id="ml183.s12"><h5>Bir1/2 assay materials</h5><ol><li class="half_rhythm"><div>Bir1/2 protein and rhodamine-SMAC peptide (AVPIAQK-rhodamine) were provided by Prof. John Reed (Burnham Institute for Medical Research, San Diego, CA)</div></li><li class="half_rhythm"><div>Assay buffer: 31.25 mM HEPES-NaOH, pH 7.5, 1.25 mM TCEP, 0.00625% Tween 20.</div></li><li class="half_rhythm"><div>Bir1/2 working solution contained 2.5 μM Bir1/2 in the assay buffer.</div></li><li class="half_rhythm"><div>Rhodamine-SMAC working solution contained 50 nM FITC-Tr3-R8 peptide in the assay buffer.</div></li></ol></div><div id="ml183.s13"><h5>Bir1/2 protocol</h5><ol><li class="half_rhythm"><div>4 µL of serially diluted compounds in DMSO were dispensed in columns 3–22 of Greiner 384-well black small-volume plates (784076). Compounds were serially diluted in DMSO to have duplicate 10-point curves with 2-fold dilution between concentrations. Columns 1–2 and 23–24 were added with 4 µL of 10% DMSO.</div></li><li class="half_rhythm"><div>Positive control wells, that contained no Bir1/2, were assigned to columns 1–2 and were added 8 µL of assay buffer using WellMate bulk dispenser (Matrix).</div></li><li class="half_rhythm"><div>8 µL of Bir1/2 working solution was added to columns 3–24 using WellMate bulk dispenser (Matrix). Negative control wells that contained DMSO were assigned to columns 23–24.</div></li><li class="half_rhythm"><div>Plates were briefly spun down and incubated for 1h at room temperature.</div></li><li class="half_rhythm"><div>8 µL of Rhodamine-SMAC working solution was added to the whole plate using WellMate bulk dispenser (Matrix).</div></li><li class="half_rhythm"><div>Final concentrations of the components in the assay were as follows:</div><ol class="lower-alpha"><li class="half_rhythm"><div>25 mM HEPES-NaOH, pH 7.5, 1 mM TCEP, 0.005% Tween 20.</div></li><li class="half_rhythm"><div>20 nM Rhodamine-SMAC (columns 1–24)</div></li><li class="half_rhythm"><div>1 μM Bir1/2 (columns 2–24)</div></li><li class="half_rhythm"><div>2 % DMSO (columns 1–24</div></li><li class="half_rhythm"><div>20 μM compounds (columns 3–24)</div></li></ol></li><li class="half_rhythm"><div>Plates were incubated for 30 min at room temperature protected from direct light.</div></li><li class="half_rhythm"><div>Fluorescence polarization was measured on an EnVision plate reader (Perkin Elmer) using rhodamine filters: excitation filter - 540 nm, emission filter 590 nm, dichroic mirror - 560 nm. The signal for each well was acquired for 100 ms.</div></li><li class="half_rhythm"><div>Data analysis was performed using CBIS software (ChemInnovations, Inc).</div></li><li class="half_rhythm"><div>Fluorescence intensity of each sample was normalized to the average fluorescence intensity value of the plate negative control wells to calculate F_ratio parameter.</div></li></ol><p>195,576 compounds were tested in this assay. The average Z′ for this assay was 0.85, the signal to background ratio was 3.8, the signal to noise ratio was 46.6 and the signal window was 34.7.</p></div><div id="ml183.s14"><h5>Rationale for confirmatory, counter and selectivity assays</h5><p>SMAC is synthesized and enters the inner membrane space of mitochondria (<a class="bibr" href="#ml183.r4" rid="ml183.r4">4</a>,<a class="bibr" href="#ml183.r5" rid="ml183.r5">5</a>). The N-terminal of SMAC is cleaved off generating a new N-terminal AVPI sequence (<a class="bibr" href="#ml183.r4" rid="ml183.r4">4</a>,<a class="bibr" href="#ml183.r5" rid="ml183.r5">5</a>). On release of the activated SMAC from the mitochondria, it binds to a SMAC binding pocket on BIR2 and BIR3 competing off Caspase-3/7 and Caspase-9, respectively, and thus driving the activation of the executioner and initiator caspases by releasing the caspase from the BIR2 or BIR3 SMAC binding domains (<a class="bibr" href="#ml183.r7" rid="ml183.r7">7</a>,<a class="bibr" href="#ml183.r8" rid="ml183.r8">8</a>). It is established that the binding site of BIR3 for SMAC requires only the first 4 amino acids of activated SMAC (<a class="bibr" href="#ml183.r7" rid="ml183.r7">7</a>). The first 7 amino acids of activated SMAC are AVPIAQK (<a class="bibr" href="#ml183.r7" rid="ml183.r7">7</a>). We utilized the ɛ-amino group of lysine to couple the rhodamine to the peptide at the C-terminal. This spaced the rhodamine away from the SMAC binding pocket allowing the AVPI portion of the fluorescent probe to bind without hinderance to the BIR2 pocket yet still having the rhodamine probe tumbling with the rate of the protein.</p><p>We chose to target Caspase-3 and -7 and looked at the competition of compounds against SMAC-rhodamine in the presence of BIR1/2 where only the BIR2 domain was capable of binding SMAC-rhodamine. Development of the fluorescence polarization assay used the SMAC-7mer as a competitor for the SMAC-rhodamine (<a class="bibr" href="#ml183.r10" rid="ml183.r10">10</a>). A similar assay was developed for BIR3 and was utilized as a counter screen.</p></div></div></div><div id="ml183.s15"><h4>iii. Summary of Results</h4><p>We developed a binding assay based upon fluorescence polarization, using a short peptide representing residues from the N-terminus of activated SMAC with an attached fluorochrome. This fluorescence polarization assay (FPA) formed the basis for a high-throughput competitive displacement assay that was optimized for screening. We screened the NIH compound library using this FPA to identify chemical compounds that compete with the SMAC peptide for binding to IAPs. A secondary assay was also devised, so the hits would be independently confirmed. However, the single hit from the conventional HTS screen was very weak (> 25 μM IC<sub>50</sub>), we therefore decided to take a structure-based rational design approach to develop novel chemical probes of XIAP. Chemistry has made additional significant progress towards this goal and the results are described in section 2b-3 below.</p></div></div><div id="ml183.s16"><h3>c. Probe Optimization</h3><div id="ml183.s17"><h4>i. SAR & chemistry strategy (including structure and data) that led to the probe</h4><p>Structure based approaches to synthesis of BIR3 XIAP inhibitors are described in the literature. Novartis (ref <a class="bibr" href="#ml183.r1" rid="ml183.r1">1</a>) and Genetech (ref <a class="bibr" href="#ml183.r2" rid="ml183.r2">2</a>) have compounds that are advancing through clinical trials. There are no reports of compounds designed to inhibit the BIR2 domain of XIAP selectively over the BIR3 domain. Selective inhibition of BIR2 over BIR3 could yield valuable information about the XIAP signaling pathway. In addition, selective inhibition of BIR2 vs. BIR3 could lead to clinical candidates that have significantly different properties compared to the BIR3 selective Norvatis and Genetech clinical candidates. Our initial research efforts on the design, synthesis and evaluation of novel BIR2 selective Smac mimetics as chemical antagonists of the anti-apoptotic protein XIAP were summarized in our previous probe report for CID 25241665. Compound CID 25241665 (MLS-0391005) was selected as a Probe at that time due to its relatively good selectivity (8-fold) for BIR2 over the BIR3 binding domain of XIAP. These initial findings are the first report in the literature that selectivity of the BIR2 domain over the BIR3 domain is achievable. In the previous report, we provided a model of the key differences between the BIR2 and BIR3 protein structures at the SMAC binding site that provided a rational basis for designing BIR2 selective compounds by substituent variation of the key positions noted below in <a class="figpopup" href="/books/NBK55068/figure/ml183.f1/?report=objectonly" target="object" rid-figpopup="figml183f1" rid-ob="figobml183f1">Figure 1</a>. Comparative docking into the BIR2 and BIR3 domains rationalized the increased selectivity of this probe. Modeling studies also suggested the proline motif in <a class="figpopup" href="/books/NBK55068/figure/ml183.f1/?report=objectonly" target="object" rid-figpopup="figml183f1" rid-ob="figobml183f1">Figure 1</a> could be amenable for specificity design. As an extension of these studies, we undertook the synthesis of a second library composed of 80 new Smac mimetics which lack the conformational restriction of the prolyl group, yet probes the interaction at the differential binding pocket of BIR2 vs. BIR3 at position 3 (<a class="figpopup" href="/books/NBK55068/figure/ml183.f2/?report=objectonly" target="object" rid-figpopup="figml183f2" rid-ob="figobml183f2">Figure 2</a>). As a consequence of significantly improved potency and BIR2 selectivity of compounds from this second library, we are now able to nominate a second highly selective Probe, CID 44176346 (MLS-0412114).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml183f1" co-legend-rid="figlgndml183f1"><a href="/books/NBK55068/figure/ml183.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml183f1" rid-ob="figobml183f1"><img class="small-thumb" src="/books/NBK55068/bin/ml183f1.gif" src-large="/books/NBK55068/bin/ml183f1.jpg" alt="Figure 1. Key SAR for our first library." /></a><div class="icnblk_cntnt" id="figlgndml183f1"><h4 id="ml183.f1"><a href="/books/NBK55068/figure/ml183.f1/?report=objectonly" target="object" rid-ob="figobml183f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Key SAR for our first library. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml183f2" co-legend-rid="figlgndml183f2"><a href="/books/NBK55068/figure/ml183.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml183f2" rid-ob="figobml183f2"><img class="small-thumb" src="/books/NBK55068/bin/ml183f2.gif" src-large="/books/NBK55068/bin/ml183f2.jpg" alt="Figure 2. Key SAR for our second library." /></a><div class="icnblk_cntnt" id="figlgndml183f2"><h4 id="ml183.f2"><a href="/books/NBK55068/figure/ml183.f2/?report=objectonly" target="object" rid-ob="figobml183f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Key SAR for our second library. </p></div></div><p><a class="figpopup" href="/books/NBK55068/figure/ml183.f1/?report=objectonly" target="object" rid-figpopup="figml183f1" rid-ob="figobml183f1">Figure 1</a> summarizes the evolution of the SAR studies for the synthesis of our first library of Smac mimetics. In addition to the chemical modifications at positions P1, P2, N-terminus and C-terminus, we decided to extend our SAR studies to the P3 position of the parent tripeptide (3-mer) (<a class="figpopup" href="/books/NBK55068/figure/ml183.f2/?report=objectonly" target="object" rid-figpopup="figml183f2" rid-ob="figobml183f2">Figure 2</a>).</p><p>Specific analogues were synthesized and the resulting new candidates were evaluated for binding to the BIR2 and BIR3 domains of XIAP using fluorescence polarization (FP) assays. The IC<sub>50</sub> values obtained are summarized in <a class="figpopup" href="/books/NBK55068/table/ml183.t3/?report=objectonly" target="object" rid-figpopup="figml183t3" rid-ob="figobml183t3">Table 3</a>. Compound CID 44176336 (MLS-0391057), which contains an indole group at the C-terminus (R<sup>4</sup>) showed improved binding affinity (IC<sub>50</sub> = 2.0 μM) and 7-fold selectivity for BIR2. Substitution of the proline group at P3 for a valine residue [<i>e.g</i>. CID 44176342, CID 44176338, and CID 44176344 (MLS-0412059, MLS-0391058 and MLS-0412062, respectively)] showed improved selectivity for the BIR2 domain. We found that hydrazine [<i>e.g</i>. CID 44176338, CID 44176344, and CID 44176334 (MLS-0391058, MLS-0412062 and MLS-0391056, respectively)] and alpha-naphthyl [<i>e.g</i>. CID 44176342 (MLS-0412059), CID 44176340 (MLS-0412053)] C-terminus capping groups were optimal for BIR2 potency and selectivity. Incorporation of an alanine residue at P3 [<i>e.g</i>. CID 44176334 (MLS-0391056), CID 44176340 (MLS-0412053)] also resulted in similar or improved selectivity for the BIR2 domain, while maintaining the potency observed with the aforementioned candidates. We also studied the effect of substitution at the N-terminus on potency and selectivity. Compound CID 44176346 (MLS-0412114), which lacks a substituent at the N-termimus, showed extraordinary binding affinity (IC<sub>50</sub>= 1.8 μM) and selectivity (57-fold) for the BIR2 domain. However in our cellular based assay this compound is considerably less active than MLS-0412053. MLS-0412053 was selected on the basis of its potency, greatly improved selectivity (49.4 fold) for the BIR2 domain and cellular based activity as our new XIAP Probe. MLS-0412053 (15.0 mg) was submitted to the NCI 60 <i>in vitro</i> screen on September 21, 2010.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml183t3"><a href="/books/NBK55068/table/ml183.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml183t3" rid-ob="figobml183t3"><img class="small-thumb" src="/books/NBK55068/table/ml183.t3/?report=thumb" src-large="/books/NBK55068/table/ml183.t3/?report=previmg" alt="Table 3. Binding affinity to the XIAP-BIR1/2 and BIR3 domains for representative examples." /></a><div class="icnblk_cntnt"><h4 id="ml183.t3"><a href="/books/NBK55068/table/ml183.t3/?report=objectonly" target="object" rid-ob="figobml183t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Binding affinity to the XIAP-BIR1/2 and BIR3 domains for representative examples. </p></div></div><div id="ml183.f3" class="figure bk_fig"><div class="graphic"><img src="/books/NBK55068/bin/ml183f3.jpg" alt="Figure 3. A docking model of new probe molecule CID 44176340, that provides a rational explanation of the improved selectivity of this new probe." /></div><h3><span class="label">Figure 3</span><span class="title">A docking model of new probe molecule CID 44176340, that provides a rational explanation of the improved selectivity of this new probe</span></h3><div class="caption"><p>The Glide program (Schrodinger LLC) was used for flexible protein-ligand docking of the probe molecule. The Bir2 and Bir3 protein structures are rendered as molecular surfaces colored according to cavity depth (red – deep, blue – shallow)</p></div></div><p>The modeling results suggest that the probe compound CID 44176340 (MLS-44176340) adopts two different binding modes in BIR2 and BIR3 due to the differences of the two binding sites. The rigid naphthalene group of the compound cannot fit as well as the Ile side chain of the AVPI peptide into the right sub-pocket in BIR3. The replacement of the proline with alanine also eliminates the favorable van der Waals interaction between the proline of AVPI and the protein residue Trp323 in BIR3. Taken together, these two structure-based modifications make the compound selective towards BIR2.</p><p>In summary, the SAR studies undertaken around our standard tripeptide (<a class="figpopup" href="/books/NBK55068/figure/ml183.f2/?report=objectonly" target="object" rid-figpopup="figml183f2" rid-ob="figobml183f2">Figure 2</a>) have established that the presence of an <i>N</i>-methylalanine residue at P3 is a key structural element to improve the BIR1/2 selectivity and cellular based activity of the resulting Smac mimetics.</p></div></div></div><div id="ml183.s18"><h2 id="_ml183_s18_">3. Probe</h2><div id="ml183.s19"><h3>a. Chemical name of probe compound</h3><p>Formic Acid; (2S)-3-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-N-[(2S)-1-(naphthalen-1-ylamino)-1-oxopropan-2-yl]butanamide <b>[<a href="/pcsubstance/?term=ML183[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML183</a>]</b></p></div><div id="ml183.s20"><h3>b. Probe chemical structure</h3><div id="ml183.fu2" class="figure"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu9.jpg" alt="Image ml183fu9" /></div></div></div><div id="ml183.s21"><h3>c. Structural verification information of probe SID</h3><p>Probe SID number is <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164169" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85164169</a></p><p>Purity: >95% (HPLC-MS)</p><div id="ml183.fu3" class="figure"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu10.jpg" alt="Image ml183fu10" /></div></div><div id="ml183.fu4" class="figure"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu11.jpg" alt="Image ml183fu11" /></div></div></div><div id="ml183.s22"><h3>d. PubChem CID (corresponding to the SID)</h3><p>PubChem CID is 44176340 (corresponding to <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164169" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85164169</a>)</p></div><div id="ml183.s23"><h3>e. Availability from a vendor</h3><p>This probe is not commercially available from vendors</p></div><div id="ml183.s24"><h3>f. MLS# of probe molecule and related samples that were submitted to the SMR collection</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml183t4"><a href="/books/NBK55068/table/ml183.t4/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml183t4" rid-ob="figobml183t4"><img class="small-thumb" src="/books/NBK55068/table/ml183.t4/?report=thumb" src-large="/books/NBK55068/table/ml183.t4/?report=previmg" alt="Table 5. Submission of Probe and analogs." /></a><div class="icnblk_cntnt"><h4 id="ml183.t4"><a href="/books/NBK55068/table/ml183.t4/?report=objectonly" target="object" rid-ob="figobml183t4">Table 5</a></h4><p class="float-caption no_bottom_margin">Submission of Probe and analogs. </p></div></div></div><div id="ml183.s25"><h3>g. Mode of action for biological activity of probe</h3><p>The reported probe mimics the binding of a single AVPI binding motif to the BIR1/2 domain of XIAP.</p><p>Additionally the probe was found to promote cell survival against a challenge by rhTRAIL, an inducer of cell death (see two graphs below). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in a wide variety of tumor cells, while it has no toxicity for the majority of normal cells. MDA-MB-231 breast carcinoma cells (<a class="figpopup" href="/books/NBK55068/figure/ml183.f4/?report=objectonly" target="object" rid-figpopup="figml183f4" rid-ob="figobml183f4">Fig. 4a</a>: CC50>100 ng/mL) or HeLa cervical cancer cells (<a class="figpopup" href="/books/NBK55068/figure/ml183.f4/?report=objectonly" target="object" rid-figpopup="figml183f4" rid-ob="figobml183f4">Fig. 4b</a>: CC50 >100 ng/mL) or pre-treated with 5 μM of the probe CID 44176340 (MLS-0412053) for 4 hours showed a pronounced loss of cell viability upon 20 hour treatment with increasing concentrations of rhTRAIL for MDA-MB-231 (<a class="figpopup" href="/books/NBK55068/figure/ml183.f4/?report=objectonly" target="object" rid-figpopup="figml183f4" rid-ob="figobml183f4">Fig. 4a</a>: CC50 ~ 1 ng/ML) and HeLa (<a class="figpopup" href="/books/NBK55068/figure/ml183.f4/?report=objectonly" target="object" rid-figpopup="figml183f4" rid-ob="figobml183f4">Fig. 4b</a>: CC50 ~ 2 ng/mL)cells, a sensitization of these cells to TRAIL of > 100 and >50-fold, respectively. The same cells treated with vehicle before TRAIL as above were mostly refractory to the observed apoptosis induction showing only partial loss of viability, only at the highest concentrations of TRAIL tested. Indeed the use of relatively non-toxic agents as TRAIL sensitizers is envisaged to allow less toxic doses of TRAIL to be used in a clinical setting.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml183f4" co-legend-rid="figlgndml183f4"><a href="/books/NBK55068/figure/ml183.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml183f4" rid-ob="figobml183f4"><img class="small-thumb" src="/books/NBK55068/bin/ml183f4.gif" src-large="/books/NBK55068/bin/ml183f4.jpg" alt="Figure 4. TRAIL Sensitization Studies of Cancer Cells Pre-Treated with Probe CID 44176340 (MLS-0412053) [ML183]." /></a><div class="icnblk_cntnt" id="figlgndml183f4"><h4 id="ml183.f4"><a href="/books/NBK55068/figure/ml183.f4/?report=objectonly" target="object" rid-ob="figobml183f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">TRAIL Sensitization Studies of Cancer Cells Pre-Treated with Probe CID 44176340 (MLS-0412053) [ML183]. MDA-MB-231 breast carcinoma (<i>A</i>) or HeLa cervical cancer (<i>B</i>) cells were pre-treated with vehicle (blue curve) or probe ML183 (magenta curve) at 5 µM <a href="/books/NBK55068/figure/ml183.f4/?report=objectonly" target="object" rid-ob="figobml183f4">(more...)</a></p></div></div></div><div id="ml183.s26"><h3>h. Detailed synthetic pathway for making probe</h3><div id="ml183.f5" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Scheme%201.%20Synthesis%20of%20probe%20CID%2044176340.&p=BOOKS&id=55068_ml183f5.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK55068/bin/ml183f5.jpg" alt="Scheme 1. Synthesis of probe CID 44176340." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of probe CID 44176340</span></h3></div></div><div id="ml183.s27"><h3>i. Probe properties (solubility, absorbance/fluorescence, reactivity, toxicity, etc.)</h3><p>Our probe has demonstrated potent binding affinity and selectivity for BIR2 domain of XIAP, as assessed by a BIR1/2 interaction assay and modeling studies.</p><p><i>In Vitro</i> Pharmacology Profiles of Probe CID 44176340 (<i>See</i>
|
|
<a class="figpopup" href="/books/NBK55068/table/ml183.t5/?report=objectonly" target="object" rid-figpopup="figml183t5" rid-ob="figobml183t5">Table 8</a>
|
|
<i>below</i>). The probe molecule, CID 44176340 was evaluated in a detailed in vitro pharmacology screen and has excellent solubility at all pH’s tested.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml183t5"><a href="/books/NBK55068/table/ml183.t5/?report=objectonly" target="object" title="Table 8" class="img_link icnblk_img figpopup" rid-figpopup="figml183t5" rid-ob="figobml183t5"><img class="small-thumb" src="/books/NBK55068/table/ml183.t5/?report=thumb" src-large="/books/NBK55068/table/ml183.t5/?report=previmg" alt="Table 8. Summary of in vitro ADMET/PK Properties of West Nile Virus Inhibitor Probes." /></a><div class="icnblk_cntnt"><h4 id="ml183.t5"><a href="/books/NBK55068/table/ml183.t5/?report=objectonly" target="object" rid-ob="figobml183t5">Table 8</a></h4><p class="float-caption no_bottom_margin">Summary of <i>in vitro</i> ADMET/PK Properties of West Nile Virus Inhibitor Probes. </p></div></div><p>The PAMPA (<b>P</b>arallel <b>A</b>rtificial <b>M</b>embrane <b>P</b>ermeability <b>A</b>ssay) assay is used as an <i>in vitro</i> model of passive, transcellular permeability. An artificial membrane immobilized on a filter is placed between a donor and acceptor compartment. At the start of the test, drug is introduced in the donor compartment. Following the permeation period, the concentration of drug in the donor and acceptor compartments is measured using UV spectroscopy. In this assay CID 44176340 has fair to excellent permeability at various pHs.</p><p>Plasma Protein Binding is a measure of a drug’s efficiency to bind to the proteins within <i>blood plasma</i>. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Highly plasma protein bound drugs are confined to the vascular space, thereby having a relatively low volume of distribution. In contrast, drugs that remain largely unbound in plasma are generally available for distribution to other organs and tissues. CID 44176340 is highly bound (91–95 %) in human plasma and in mouse plasma it shows good binding (66 – 75 %).</p><p>Plasma Stability is a measure of the stability of small molecules and peptides in plasma and is an important parameter, which strongly can influence the <i>in vivo</i> efficacy of a test compound. Drug candidates are exposed in plasma to enzymatic processes (proteinases, esterases), and they can undergo intramolecular rearrangement or bind irreversibly (covalently) to proteins. CID 44176340 shows very good stability (64 – 71 %) in both human and mouse plasma.</p><p>The microsomal stability assay is commonly used to rank compounds according to their metabolic stability. This assay addresses the pharmacologic question of how long the parent compound will remain circulating in plasma within the body. CID 4417634 shows excellent hepatic microsome stability (84 – 91 %) in both human and mouse liver homogenates.</p><p>CID 44176340 shows low levels of toxicity toward human hepatocyctes in our assay.</p></div><div id="ml183.s28"><h3>j. Properties Computed from Structure</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml183t6"><a href="/books/NBK55068/table/ml183.t6/?report=objectonly" target="object" title="Table 7" class="img_link icnblk_img figpopup" rid-figpopup="figml183t6" rid-ob="figobml183t6"><img class="small-thumb" src="/books/NBK55068/table/ml183.t6/?report=thumb" src-large="/books/NBK55068/table/ml183.t6/?report=previmg" alt="Table 7. Properties computed from Structure." /></a><div class="icnblk_cntnt"><h4 id="ml183.t6"><a href="/books/NBK55068/table/ml183.t6/?report=objectonly" target="object" rid-ob="figobml183t6">Table 7</a></h4><p class="float-caption no_bottom_margin">Properties computed from Structure. </p></div></div></div></div><div id="ml183.s29"><h2 id="_ml183_s29_">4. Appendices</h2><div id="ml183.s30"><h3>a. Comparative data on (1) probe, (2) similar compound structures (establishing SAR) and (3) prior probes</h3><p>Bir1/2 vs Bir3 potency and selectivity data for 153 additional compounds are shown in <a class="figpopup" href="/books/NBK55068/table/ml183.t7/?report=objectonly" target="object" rid-figpopup="figml183t7" rid-ob="figobml183t7">Table A1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml183t7"><a href="/books/NBK55068/table/ml183.t7/?report=objectonly" target="object" title="Table A1" class="img_link icnblk_img figpopup" rid-figpopup="figml183t7" rid-ob="figobml183t7"><img class="small-thumb" src="/books/NBK55068/table/ml183.t7/?report=thumb" src-large="/books/NBK55068/table/ml183.t7/?report=previmg" alt="Table A1. Bir1/2 vs Bir3 potency and selectivity data for 153 additional compounds." /></a><div class="icnblk_cntnt"><h4 id="ml183.t7"><a href="/books/NBK55068/table/ml183.t7/?report=objectonly" target="object" rid-ob="figobml183t7">Table A1</a></h4><p class="float-caption no_bottom_margin">Bir1/2 vs Bir3 potency and selectivity data for 153 additional compounds. </p></div></div></div><div id="ml183.s31"><h3>b. Comparative data showing probe specificity for target</h3><p>A similar probe has been described in the literature (<a class="bibr" href="#ml183.r9" rid="ml183.r9">9</a>,<a class="bibr" href="#ml183.r10" rid="ml183.r10">10</a>,<a class="bibr" href="#ml183.r11" rid="ml183.r11">11</a>). In this case, a fluorescein molecule is coupled to the SMAC peptide. In this study rhodamine was preferred since it was further red shifted than fluorescein allowing for less sensitivity in the assay to compounds, which are auto-fluorescent.</p></div></div><div id="ml183.reflist"><h2 id="_ml183_reflist_">5. Bibliography</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml183.r1">Thompson CB. Apoptosis in the pathogenesis and treatment of disease. <span><span class="ref-journal">Science. </span>1995;<span class="ref-vol">267</span>:1456.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7878464" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7878464</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml183.r2">Riedl SJ, Shi Y. Molecular mechanisms of caspase regulation during apoptosis. <span><span class="ref-journal">Nature Reviews. Molecular Cell Biology. </span>2004;<span class="ref-vol">5</span>:897.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15520809" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15520809</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml183.r3">Deveraux QL, Reed JC. IAP family proteins: Suppressors of apoptosis. <span><span class="ref-journal">Genes Dev. </span>1999;<span class="ref-vol">13</span>:239.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9990849" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9990849</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml183.r4">Du C, Fang M, Li Y, Li L, Wang X. SMAC, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. <span><span class="ref-journal">Cell. </span>2000;<span class="ref-vol">102</span>:33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10929711" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10929711</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml183.r5">Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL. Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins. <span><span class="ref-journal">Cell. </span>2000;<span class="ref-vol">102</span>:43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10929712" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10929712</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml183.r6">Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. <span><span class="ref-journal">Molecular Cell. </span>2001;<span class="ref-vol">8</span>:613.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11583623" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11583623</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml183.r7">Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Hermann J, Wu JC, Fesik SW. Structural basis for binding of SMAC/DIABLO to the BIR3 domain. <span><span class="ref-journal">Nature. </span>2000;<span class="ref-vol">408</span>:1004.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11140637" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11140637</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml183.r8">Huang Y, Rich RL, Myszka DG, Wu H. Requirement of both the second and third domains for the relief of X-linked inhibitor of apoptosis protein (XIAP)-mediated caspase inhibition by SMAC. <span><span class="ref-journal">J. Biol. Chem. </span>2003;<span class="ref-vol">278</span>:49517.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14512414" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14512414</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml183.r9">Glover CJ, Hite K, DeLosh R, Scudiero DA, Fivash MJ, Smith LR, Fisher RJ, Wu J-W, Shi Y, Kipp RA, McLendon GL, Sausville EA, Shoemaker RH. A high-throughput screen for identification of molecular mimics of SMAC-DIABLO utilizing a fluorescence polarization assay. <span><span class="ref-journal">Anal. Biochem. </span>2003;<span class="ref-vol">320</span>:157.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12927820" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12927820</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml183.r10">Nikolovska-Coleska Z, Wang R, Fang X, Pan H, Tomita Y, Li P, Roller PP, Krajewski K, Saito NG, Stuckey JA, Wang S. Development and optimization of a binding assay for XIAP BIR3 domain using fluorescence polarization. <span><span class="ref-journal">Anal. Biochem. </span>2004;<span class="ref-vol">332</span>:261.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15325294" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15325294</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml183.r11">Oost TK, Sun C, Armstrong RC, Al-Assaad A-S, Betz SF, Deckwerth TL, Ding H, Elmore SW, Meadows RP, Olejniczak ET, Oleksijew A, Olterdorf T, Rosenberg SH, Shoemaker AR, Tomaselli KJ, Zou H, Fesik SW. Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. <span><span class="ref-journal">J. Med. Chem. </span>2004;<span class="ref-vol">47</span>:4417.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15317454" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15317454</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK55068_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Marcos Lopez</span>, <span itemprop="author">Kate Welsh</span>, <span itemprop="author">Hongbin Yuan</span>, <span itemprop="author">Derek Stonich</span>, <span itemprop="author">Ying Su</span>, <span itemprop="author">Xochella Garcia</span>, <span itemprop="author">Michael Cuddy</span>, <span itemprop="author">Richard Houghten</span>, <span itemprop="author">Eduard Sergienko</span>, <span itemprop="author">John C Reed</span>, <span itemprop="author">Robert Ardecky</span>, <span itemprop="author">Santhi Reddy</span>, <span itemprop="author">Darren Finlay</span>, <span itemprop="author">Kristiina Vuori</span>, <span itemprop="author">Shakeela Dad</span>, <span itemprop="author">Thomas DY Chung</span>, and <span itemprop="author">Nicholas DP Cosford</span>.</p><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">September 1, 2009</span>; Last Update: <span itemprop="dateModified">February 10, 2011</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Lopez M, Welsh K, Yuan H, et al. Antagonists of IAP-family anti-apoptotic proteins - Probe 2. 2009 Sep 1 [Updated 2011 Feb 10]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml200/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml170/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml183fu1"><div id="ml183.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK55068/bin/ml183fu1.jpg" alt="Image ml183fu1" /></div></div></article><article data-type="table-wrap" id="figobml183tu1"><div id="ml183.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55068/table/ml183.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml183.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml183.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th id="hd_h_ml183.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml183.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (nM) [SID, AID]</th><th id="hd_h_ml183.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml183.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (μM) [SID, AID]</th><th id="hd_h_ml183.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity</th><th id="hd_h_ml183.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay(s) Name: IC50/EC50 (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml183.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID 44176340/<b><a href="/pcsubstance/?term=ML183[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML183</a></b> (Formic acid salt)</td><td headers="hd_h_ml183.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BIR1/2<br />XIAP</td><td headers="hd_h_ml183.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50 2200 (nM)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164169" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85164169</a>/<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1722" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1722</a></td><td headers="hd_h_ml183.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BIR3</td><td headers="hd_h_ml183.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50 108.6 (µM)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164169" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85164169</a>/<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1750" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 1750</a></td><td headers="hd_h_ml183.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">49.4X</td><td headers="hd_h_ml183.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">N/A</td></tr><tr><td headers="hd_h_ml183.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><i>CID 46916243</i><br /><i><a href="/pcsubstance/?term=ML183[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML183</a> (TFA salt)</i></td><td headers="hd_h_ml183.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BIR1/2<br />XIAP</td><td headers="hd_h_ml183.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50 4617 (nM)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99380920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99380920</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488957" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488957</a></td><td headers="hd_h_ml183.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BIR3</td><td headers="hd_h_ml183.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50 137.2 (µM)<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/899380920" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 899380920</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488963" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488963</a></td><td headers="hd_h_ml183.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">29.7X</td><td headers="hd_h_ml183.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">N/A</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml183t1"><div id="ml183.t1" class="table"><h3><span class="label">Table 1</span><span class="title">PubChem Assay Summaries for Probe project</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55068/table/ml183.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml183.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml183.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChemBioAssay Name</th><th id="hd_h_ml183.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AIDs</th><th id="hd_h_ml183.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe Type</th><th id="hd_h_ml183.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Type</th><th id="hd_h_ml183.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Format</th><th id="hd_h_ml183.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Detection & well format</th></tr></thead><tbody><tr><td headers="hd_h_ml183.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Chemical Antagonists IAP-family anti-apoptotic proteins—primary screen and HTS/DPI liquid hit confirms</td><td headers="hd_h_ml183.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1018" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1018</a></td><td headers="hd_h_ml183.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml183.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary</td><td headers="hd_h_ml183.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml183.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence Polarization (384)</td></tr><tr><td headers="hd_h_ml183.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">XIAP-Bir3 for Chemical Antagonists of Bir1/2 domains of IAP-family anti-apoptotic proteins—liquid hit confirmation from DPI</td><td headers="hd_h_ml183.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1513" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1513</a></td><td headers="hd_h_ml183.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml183.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Counter screen</td><td headers="hd_h_ml183.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml183.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence Polarization (384)</td></tr><tr><td headers="hd_h_ml183.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of Antagonists of IAP-family anti-apoptotic proteins –Dry powder [Confirmatory]</td><td headers="hd_h_ml183.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1749" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1749</a></td><td headers="hd_h_ml183.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml183.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Counter screen</td><td headers="hd_h_ml183.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml183.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence Polarization (96)</td></tr><tr><td headers="hd_h_ml183.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of Antagonists of XIAP-Bir3 domain of IAP-family anti-apoptotic-dry powder.</td><td headers="hd_h_ml183.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1750" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1750</a></td><td headers="hd_h_ml183.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml183.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Counter screen</td><td headers="hd_h_ml183.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml183.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence Polarization (96)</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml183t2"><div id="ml183.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Reagents used for the uHTS experiments</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55068/table/ml183.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml183.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml183.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Reagents</th><th id="hd_h_ml183.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Vendor</th></tr></thead><tbody><tr><td headers="hd_h_ml183.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Expression plasmid for BIR12 of XIAP cloned</td><td headers="hd_h_ml183.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dr. Reed’s laboratory</td></tr><tr><td headers="hd_h_ml183.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BIR1/2 protein</td><td headers="hd_h_ml183.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Purified in Dr. Reed’s laboratory</td></tr><tr><td headers="hd_h_ml183.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1 M Hepes buffer</td><td headers="hd_h_ml183.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Qmega Scientific, Inc</td></tr><tr><td headers="hd_h_ml183.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TCEP</td><td headers="hd_h_ml183.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma</td></tr><tr><td headers="hd_h_ml183.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.5 M Tween 20</td><td headers="hd_h_ml183.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BIO-RAD</td></tr><tr><td headers="hd_h_ml183.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SMAC-rhodamine</td><td headers="hd_h_ml183.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Synthesized in Dr. Houghten’s laboratory at The Torrey Pines Institute for Molecular Studies (TPIMS)</td></tr><tr><td headers="hd_h_ml183.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SMAC-7mer</td><td headers="hd_h_ml183.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Synthesized in Dr. Houghten’s laboratory at The Torrey Pines Institute for Molecular Studies (TPIMS)</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml183f1"><div id="ml183.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55068/bin/ml183f1.jpg" alt="Figure 1. Key SAR for our first library." /></div><h3><span class="label">Figure 1</span><span class="title">Key SAR for our first library</span></h3></div></article><article data-type="fig" id="figobml183f2"><div id="ml183.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55068/bin/ml183f2.jpg" alt="Figure 2. Key SAR for our second library." /></div><h3><span class="label">Figure 2</span><span class="title">Key SAR for our second library</span></h3></div></article><article data-type="table-wrap" id="figobml183t3"><div id="ml183.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Binding affinity to the XIAP-BIR1/2 and BIR3 domains for representative examples</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55068/table/ml183.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml183.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml183.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ID</th><th id="hd_h_ml183.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th id="hd_h_ml183.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem CID</th><th id="hd_h_ml183.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PubChem SID</th><th id="hd_h_ml183.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BIR 1/2 IC<sub>50</sub> (μM)</th><th id="hd_h_ml183.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BIR3 IC<sub>50</sub> (μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml183.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0391057</td><td headers="hd_h_ml183.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu2.jpg" alt="Image ml183fu2.jpg" /></div></td><td headers="hd_h_ml183.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44176336</td><td headers="hd_h_ml183.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164167" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164167</a></td><td headers="hd_h_ml183.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.0</td><td headers="hd_h_ml183.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.3</td></tr><tr><td headers="hd_h_ml183.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0412059</td><td headers="hd_h_ml183.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu3.jpg" alt="Image ml183fu3.jpg" /></div></td><td headers="hd_h_ml183.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44176342</td><td headers="hd_h_ml183.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164170</a></td><td headers="hd_h_ml183.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.9</td><td headers="hd_h_ml183.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml183.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0391058</td><td headers="hd_h_ml183.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu4.jpg" alt="Image ml183fu4.jpg" /></div></td><td headers="hd_h_ml183.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44176338</td><td headers="hd_h_ml183.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164168" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164168</a></td><td headers="hd_h_ml183.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.0</td><td headers="hd_h_ml183.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">167.9</td></tr><tr><td headers="hd_h_ml183.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0412062</td><td headers="hd_h_ml183.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu5.jpg" alt="Image ml183fu5.jpg" /></div></td><td headers="hd_h_ml183.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44176344</td><td headers="hd_h_ml183.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164171" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164171</a></td><td headers="hd_h_ml183.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.9</td><td headers="hd_h_ml183.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml183.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0391056</td><td headers="hd_h_ml183.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu6.jpg" alt="Image ml183fu6.jpg" /></div></td><td headers="hd_h_ml183.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44176334</td><td headers="hd_h_ml183.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164166" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164166</a></td><td headers="hd_h_ml183.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.7</td><td headers="hd_h_ml183.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">132.5</td></tr><tr><td headers="hd_h_ml183.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412053</b></td><td headers="hd_h_ml183.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu7.jpg" alt="Image ml183fu7.jpg" /></div></td><td headers="hd_h_ml183.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44176340</td><td headers="hd_h_ml183.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164169" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164169</a></td><td headers="hd_h_ml183.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.2</td><td headers="hd_h_ml183.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">108.6</td></tr><tr><td headers="hd_h_ml183.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0412114</td><td headers="hd_h_ml183.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu8.jpg" alt="Image ml183fu8.jpg" /></div></td><td headers="hd_h_ml183.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44176346</td><td headers="hd_h_ml183.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164172" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164172</a></td><td headers="hd_h_ml183.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.8</td><td headers="hd_h_ml183.t3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">102.7</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml183f3"><div id="ml183.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55068/bin/ml183f3.jpg" alt="Figure 3. A docking model of new probe molecule CID 44176340, that provides a rational explanation of the improved selectivity of this new probe." /></div><h3><span class="label">Figure 3</span><span class="title">A docking model of new probe molecule CID 44176340, that provides a rational explanation of the improved selectivity of this new probe</span></h3><div class="caption"><p>The Glide program (Schrodinger LLC) was used for flexible protein-ligand docking of the probe molecule. The Bir2 and Bir3 protein structures are rendered as molecular surfaces colored according to cavity depth (red – deep, blue – shallow)</p></div></div></article><article data-type="fig" id="figobml183fu2"><div id="ml183.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK55068/bin/ml183fu9.jpg" alt="Image ml183fu9" /></div></div></article><article data-type="fig" id="figobml183fu3"><div id="ml183.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK55068/bin/ml183fu10.jpg" alt="Image ml183fu10" /></div></div></article><article data-type="fig" id="figobml183fu4"><div id="ml183.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK55068/bin/ml183fu11.jpg" alt="Image ml183fu11" /></div></div></article><article data-type="table-wrap" id="figobml183t4"><div id="ml183.t4" class="table"><h3><span class="label">Table 5</span><span class="title">Submission of Probe and analogs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55068/table/ml183.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml183.t4_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml183.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe/analog</th><th id="hd_h_ml183.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">DPI ML#</th><th id="hd_h_ml183.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-# (BCCG#)</th><th id="hd_h_ml183.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th id="hd_h_ml183.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th id="hd_h_ml183.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Source (vendor or BCCG syn)</th><th id="hd_h_ml183.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Amt (mg)</th><th id="hd_h_ml183.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Date ordered/submitted</th></tr></thead><tbody><tr><td headers="hd_h_ml183.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe <b>[<a href="/pcsubstance/?term=ML183[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML183</a>]</b></td><td headers="hd_h_ml183.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS002477156</td><td headers="hd_h_ml183.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0412053</td><td headers="hd_h_ml183.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44176340</td><td headers="hd_h_ml183.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164169" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164169</a></td><td headers="hd_h_ml183.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BCCG syn</td><td headers="hd_h_ml183.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">19.2</td><td headers="hd_h_ml183.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">09/01/09</td></tr><tr><td headers="hd_h_ml183.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog1</td><td headers="hd_h_ml183.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002477154</td><td headers="hd_h_ml183.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0391057</td><td headers="hd_h_ml183.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44176336</td><td headers="hd_h_ml183.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164167" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164167</a></td><td headers="hd_h_ml183.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml183.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21.0</td><td headers="hd_h_ml183.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">09/01/09</td></tr><tr><td headers="hd_h_ml183.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog2</td><td headers="hd_h_ml183.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002477155</td><td headers="hd_h_ml183.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0412059</td><td headers="hd_h_ml183.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44176342</td><td headers="hd_h_ml183.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164170" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164170</a></td><td headers="hd_h_ml183.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml183.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18.6</td><td headers="hd_h_ml183.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">09/01/09</td></tr><tr><td headers="hd_h_ml183.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog3</td><td headers="hd_h_ml183.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002477157</td><td headers="hd_h_ml183.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0391058</td><td headers="hd_h_ml183.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44176338</td><td headers="hd_h_ml183.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164168" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164168</a></td><td headers="hd_h_ml183.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml183.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">19.3</td><td headers="hd_h_ml183.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">09/01/09</td></tr><tr><td headers="hd_h_ml183.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog4</td><td headers="hd_h_ml183.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002477159</td><td headers="hd_h_ml183.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0412062</td><td headers="hd_h_ml183.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44176344</td><td headers="hd_h_ml183.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164171" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164171</a></td><td headers="hd_h_ml183.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml183.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21.3</td><td headers="hd_h_ml183.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">09/01/09</td></tr><tr><td headers="hd_h_ml183.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog5</td><td headers="hd_h_ml183.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002477158</td><td headers="hd_h_ml183.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0391056</td><td headers="hd_h_ml183.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44176334</td><td headers="hd_h_ml183.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164166" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164166</a></td><td headers="hd_h_ml183.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml183.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20.8</td><td headers="hd_h_ml183.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">09/01/09</td></tr><tr><td headers="hd_h_ml183.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog6</td><td headers="hd_h_ml183.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS002477153</td><td headers="hd_h_ml183.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0412114</td><td headers="hd_h_ml183.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44176346</td><td headers="hd_h_ml183.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85164172" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85164172</a></td><td headers="hd_h_ml183.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BCCG syn</td><td headers="hd_h_ml183.t4_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22.6</td><td headers="hd_h_ml183.t4_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">09/01/09</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml183f4"><div id="ml183.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK55068/bin/ml183f4.jpg" alt="Figure 4. TRAIL Sensitization Studies of Cancer Cells Pre-Treated with Probe CID 44176340 (MLS-0412053) [ML183]." /></div><h3><span class="label">Figure 4</span><span class="title">TRAIL Sensitization Studies of Cancer Cells Pre-Treated with Probe CID 44176340 (MLS-0412053) [<a href="/pcsubstance/?term=ML183[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML183</a>]</span></h3><div class="caption"><p>MDA-MB-231 breast carcinoma (<b>A</b>) or HeLa cervical cancer (<b>B</b>) cells were pre-treated with vehicle (blue curve) or probe <a href="/pcsubstance/?term=ML183[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML183</a> (magenta curve) at 5 µM final concentration in standard tissue culture media for 4 h at 37°C in 5% CO<sub>2</sub> in 96-wells (E&K Scientific, Santa Clara, CA),. Serially diluted rhTRAIL (Calbiochem, La Jolla, CA) is added to the cells to the final concentration described and the cells are incubated for a further 20 h at 37°C in 5% CO<sub>2</sub>. Cells are removed removed from 37°C and allowed to equilibrate to r.t. for 30 mins before addition of (1/2 volume) of room temperature CellTiter-Glo™ assay reagent (Promega Corp, Madison, WI). Plates are orbitally shaken at 150 rpm for 10 mins before luminescence is read with Gen5 software on a Biotek Synergy 2 plate reader. Data are plotted a relative to vehicle only (no probe, no rhTRAIL) controls.</p></div></div></article><article data-type="fig" id="figobml183f5"><div id="ml183.f5" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Scheme%201.%20Synthesis%20of%20probe%20CID%2044176340.&p=BOOKS&id=55068_ml183f5.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK55068/bin/ml183f5.jpg" alt="Scheme 1. Synthesis of probe CID 44176340." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of probe CID 44176340</span></h3></div></article><article data-type="table-wrap" id="figobml183t5"><div id="ml183.t5" class="table"><h3><span class="label">Table 8</span><span class="title">Summary of <i>in vitro</i> ADMET/PK Properties of West Nile Virus Inhibitor Probes</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55068/table/ml183.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml183.t5_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml183.t5_1_1_1_1" rowspan="3" colspan="1" headers="hd_h_ml183.t5_1_1_1_1" style="text-align:center;vertical-align:top;">Probe CID<br />Probe ML#</th><th id="hd_h_ml183.t5_1_1_1_2" rowspan="3" colspan="1" headers="hd_h_ml183.t5_1_1_1_2" style="text-align:center;vertical-align:top;">Aqueous Solubility (μg/mL)<sup>a</sup> (@ pH)</th><th id="hd_h_ml183.t5_1_1_1_3" rowspan="3" colspan="1" headers="hd_h_ml183.t5_1_1_1_3" style="text-align:center;vertical-align:top;">PAMPA<br />Pe (×10<sup>−6</sup> cm/s)<sup>b</sup> (@ pH)</th><th id="hd_h_ml183.t5_1_1_1_4" colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">Plasma Protein Binding (% Bound)</th><th id="hd_h_ml183.t5_1_1_1_5" rowspan="3" colspan="1" headers="hd_h_ml183.t5_1_1_1_5" style="text-align:center;vertical-align:top;">Plasma Stability<sup>c</sup><br />Human/Mouse</th><th id="hd_h_ml183.t5_1_1_1_6" rowspan="3" colspan="1" headers="hd_h_ml183.t5_1_1_1_6" style="text-align:center;vertical-align:top;">Hepatic Microsome Stability<sup>d</sup><br />Human/Mouse</th><th id="hd_h_ml183.t5_1_1_1_7" rowspan="3" colspan="1" headers="hd_h_ml183.t5_1_1_1_7" style="text-align:center;vertical-align:top;">Hepatic Toxicity<sup>e</sup><br />LC50 (μM)</th></tr><tr><th headers="hd_h_ml183.t5_1_1_1_4" id="hd_h_ml183.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Human</th><th headers="hd_h_ml183.t5_1_1_1_4" id="hd_h_ml183.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Mouse</th></tr><tr><th headers="hd_h_ml183.t5_1_1_1_4 hd_h_ml183.t5_1_1_2_1" id="hd_h_ml183.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1μM/10μM</th><th headers="hd_h_ml183.t5_1_1_1_4 hd_h_ml183.t5_1_1_2_2" id="hd_h_ml183.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1μM/10μM</th></tr></thead><tbody><tr><td headers="hd_h_ml183.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 44176340</td><td headers="hd_h_ml183.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>254 (5.0)<br />>254 (6.2)<br />>254 (7.4)</td><td headers="hd_h_ml183.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.4 (5.0)<br />2.6 (6.2)<br />11 (7.4)</td><td headers="hd_h_ml183.t5_1_1_1_4 hd_h_ml183.t5_1_1_2_1 hd_h_ml183.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">94.81/90.96</td><td headers="hd_h_ml183.t5_1_1_1_4 hd_h_ml183.t5_1_1_2_2 hd_h_ml183.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">75.05/65.96</td><td headers="hd_h_ml183.t5_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">70.82/64.80</td><td headers="hd_h_ml183.t5_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">91.02/84.04</td><td headers="hd_h_ml183.t5_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml183.tfn1"><p class="no_margin">in aqueous buffer, pH’s 5.0/6.2/7.4</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml183.tfn2"><p class="no_margin">in aqueous buffer; Donor compartment pH’s 5.0/6.2/7.4; Acceptor compartment pH 7.4</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml183.tfn3"><p class="no_margin">% remaining at 3 hr</p></div></dd></dl><dl class="bkr_refwrap"><dt>d</dt><dd><div id="ml183.tfn4"><p class="no_margin">% remaining at 1 hr</p></div></dd></dl><dl class="bkr_refwrap"><dt>e</dt><dd><div id="ml183.tfn5"><p class="no_margin">towards Fa2N-4 immortalized human hepatocytes</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml183.tfn6"><p class="no_margin">Unable to detect any compound at 1 μM</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml183t6"><div id="ml183.t6" class="table"><h3><span class="label">Table 7</span><span class="title">Properties computed from Structure</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55068/table/ml183.t6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml183.t6_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml183.t6_1_1_1_1" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">CID 44176340 [<b><a href="/pcsubstance/?term=ML183[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML183</a>]</b> (MLS-0412053)</th></tr></thead><tbody><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Weight [g/mol]</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">444.52398</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular formula</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">C<sub>23</sub>H<sub>32</sub>N<sub>4</sub>O<sub>5</sub></td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tautomer Count</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">444.23727</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MonoIsotopic Mass</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">444.23727</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Topological Polar Surface Area</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">137</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heavy Atom Count</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">32</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Formal Charge</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Complexity</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">591</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Isotope Atom Count</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Atom StereoCenter Count</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Atom StereoCenter Count</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Bond StereoCenter Count</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Bond StereoCenter Count</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Covalently-Bonded Unit Count</td><td headers="hd_h_ml183.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml183t7"><div id="ml183.t7" class="table"><h3><span class="label">Table A1</span><span class="title">Bir1/2 vs Bir3 potency and selectivity data for 153 additional compounds</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK55068/table/ml183.t7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml183.t7_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound ID</th><th id="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Structure</th><th id="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BIR1/2 IC<sub>50</sub> (μM)</th><th id="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">BIR3 IC<sub>50</sub> (μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390868</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu12.jpg" alt="Image ml183fu12.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.3 ± 4.0</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390869</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu13.jpg" alt="Image ml183fu13.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24.4 ± 11.7</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390870</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu14.jpg" alt="Image ml183fu14.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.7 ± 1.0</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.5 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390871</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu15.jpg" alt="Image ml183fu15.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16.7 ± 5.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.8 ± 0.8</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390899</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu16.jpg" alt="Image ml183fu16.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.9 ± 1.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.3 ± 0.4</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0086644</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu17.jpg" alt="Image ml183fu17.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390970</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu18.jpg" alt="Image ml183fu18.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.2 ± 0.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.7 ±0.2</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390971</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu19.jpg" alt="Image ml183fu19.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.6 ± 1.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.7 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390969</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu20.jpg" alt="Image ml183fu20.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-390969.0002</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu21.jpg" alt="Image ml183fu21.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.4 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.0 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390968</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu22.jpg" alt="Image ml183fu22.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17.9 ± 2.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.5 ± 1.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390972</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu23.jpg" alt="Image ml183fu23.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">36.3 ± 3.0</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">67.0 ± 13.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390980</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu24.jpg" alt="Image ml183fu24.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.2 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.46 ± 0.05</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390973</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu25.jpg" alt="Image ml183fu25.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22.6 ± 7.4</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.07 ± 0.02</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390977</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu26.jpg" alt="Image ml183fu26.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">23.6 ± 8.0</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.6 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390978</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu27.jpg" alt="Image ml183fu27.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17.5 ± 3.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.2 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390979</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu28.jpg" alt="Image ml183fu28.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.1 ± 0.4</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.79 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390981</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu29.jpg" alt="Image ml183fu29.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.7 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.9 ± 0.2</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390982</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu30.jpg" alt="Image ml183fu30.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.1 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.28 ± 0.03</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390983</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu31.jpg" alt="Image ml183fu31.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">153.9 ± 28.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.5 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390984</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu32.jpg" alt="Image ml183fu32.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">67.1 ± 2.6</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390987</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu33.jpg" alt="Image ml183fu33.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390986</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu34.jpg" alt="Image ml183fu34.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390988</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu35.jpg" alt="Image ml183fu35.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">36.0 ± 0.07</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390989</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu36.jpg" alt="Image ml183fu36.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390990</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu37.jpg" alt="Image ml183fu37.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390991</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu38.jpg" alt="Image ml183fu38.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390992</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu39.jpg" alt="Image ml183fu39.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390993</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu40.jpg" alt="Image ml183fu40.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">54.6 ± 1.6</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391000</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu41.jpg" alt="Image ml183fu41.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.2 ± 1.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.9 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391001</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu42.jpg" alt="Image ml183fu42.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.7 ± 1.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.98 ± 0.08</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390997</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu43.jpg" alt="Image ml183fu43.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.6 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.03 ± 0.02</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390998</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu44.jpg" alt="Image ml183fu44.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">76.5 ± 0.4</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390999</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu45.jpg" alt="Image ml183fu45.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">27.3 ± 0.8</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391005</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu46.jpg" alt="Image ml183fu46.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.0 ± 0.6</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">32.6 ± 2.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391004</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu47.jpg" alt="Image ml183fu47.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.3 ± 0.9</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.8 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391002</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu48.jpg" alt="Image ml183fu48.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.7 ± 1.9</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.53 ± 0.01</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391003</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu49.jpg" alt="Image ml183fu49.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">18.6 ± 5.9</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">19.5 ± 0.50</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391007</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu50.jpg" alt="Image ml183fu50.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.1 ± 1.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.63 ± 0.01</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391006</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu51.jpg" alt="Image ml183fu51.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.4 ± 0.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.38 ± 0.00</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391008</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu52.jpg" alt="Image ml183fu52.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391009</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu53.jpg" alt="Image ml183fu53.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391010</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu54.jpg" alt="Image ml183fu54.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12.2 ± 0.4</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.6 ± 3.0</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391011</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu55.jpg" alt="Image ml183fu55.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.3 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.9 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391012</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu56.jpg" alt="Image ml183fu56.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391013</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu57.jpg" alt="Image ml183fu57.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391014</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu58.jpg" alt="Image ml183fu58.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11.4 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">94.9 ± 20.2</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>M LS-0391015</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu59.jpg" alt="Image ml183fu59.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.5 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.7 ± 0.6</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391025</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu60.jpg" alt="Image ml183fu60.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.4 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.2 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391026</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu61.jpg" alt="Image ml183fu61.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.5 ± 0.6</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.2 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391027</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu62.jpg" alt="Image ml183fu62.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">41.0 ± 4.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.4 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391028</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu63.jpg" alt="Image ml183fu63.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11.9 ± 2.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.2 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391029</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu64.jpg" alt="Image ml183fu64.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.9 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.0 ± 0.4</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391030</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu65.jpg" alt="Image ml183fu65.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.4 ± 1.9</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">143.6 ± 27.4</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391031</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu66.jpg" alt="Image ml183fu66.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.2 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">41.6 ± 3.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391037</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu67.jpg" alt="Image ml183fu67.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.4 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">35.4 ± 1.7</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391035</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu68.jpg" alt="Image ml183fu68.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20.0 ± 2.4</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">21.1 ± 1.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391032</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu69.jpg" alt="Image ml183fu69.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.1 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10.5 ± 0.2</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391034</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu70.jpg" alt="Image ml183fu70.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.1 ± 0.6</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15.7 ± 0.2</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391036</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu71.jpg" alt="Image ml183fu71.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.9 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.5 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391057</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu72.jpg" alt="Image ml183fu72.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.0 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.3 ± 0.2</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391056</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu73.jpg" alt="Image ml183fu73.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.7 ± 0.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">132.5 ± 5.5</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391055</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu74.jpg" alt="Image ml183fu74.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391058</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu75.jpg" alt="Image ml183fu75.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.0 ± 0.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">167.9 ± 15.9</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391054</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu76.jpg" alt="Image ml183fu76.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391053</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu77.jpg" alt="Image ml183fu77.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.5 ± 0.4</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.8 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391059</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu78.jpg" alt="Image ml183fu78.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.8 ± 0.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.8 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391060</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu79.jpg" alt="Image ml183fu79.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.8 ± 1.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.85± 0.12</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391061</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu80.jpg" alt="Image ml183fu80.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.7 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22.6 ± 2.8</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391062</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu81.jpg" alt="Image ml183fu81.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.0 ± 0.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.88 ± 0.08</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391063</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu82.jpg" alt="Image ml183fu82.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24.1 ± 4.0</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412053</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu83.jpg" alt="Image ml183fu83.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.7 ± 0.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412059</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu84.jpg" alt="Image ml183fu84.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.9 ± 1.0</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412060</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu85.jpg" alt="Image ml183fu85.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.9 ± 1.5</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412061</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu86.jpg" alt="Image ml183fu86.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">114.0 ± 17.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">97.7 ± 27.0</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412062</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu87.jpg" alt="Image ml183fu87.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.9 ± 0.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412063</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu88.jpg" alt="Image ml183fu88.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.1 ± 0.4</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">54.2 ± 4.5</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412065</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu89.jpg" alt="Image ml183fu89.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.2 ± 0.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.3 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412066</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu90.jpg" alt="Image ml183fu90.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.8 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412067</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu91.jpg" alt="Image ml183fu91.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">59.6 ± 1.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412068</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu92.jpg" alt="Image ml183fu92.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10.5 ± 0.6</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412069</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu93.jpg" alt="Image ml183fu93.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11.7 ± 1.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412071</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu94.jpg" alt="Image ml183fu94.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">62.3 ± 0.5</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412070</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu95.jpg" alt="Image ml183fu95.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16.6 ± 3.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412072</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu96.jpg" alt="Image ml183fu96.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412073</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu97.jpg" alt="Image ml183fu97.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412082</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu98.jpg" alt="Image ml183fu98.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">182.2 ± 20.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">34.4 ± 3.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412083</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu99.jpg" alt="Image ml183fu99.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65.3 ± 9.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">43.2 ± 0.4</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412089</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu100.jpg" alt="Image ml183fu100.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412090</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu101.jpg" alt="Image ml183fu101.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412098</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu102.jpg" alt="Image ml183fu102.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.0 ± 0.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">87.5 ± 5.5</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412113</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu103.jpg" alt="Image ml183fu103.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.3 ± 0.6</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">105.8 ± 2.2</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412114</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu104.jpg" alt="Image ml183fu104.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.8 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">102.7 ± 6.9</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412115</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu105.jpg" alt="Image ml183fu105.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>BIM-0206962</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu106.jpg" alt="Image ml183fu106.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390970.0002</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu107.jpg" alt="Image ml183fu107.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412127</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu108.jpg" alt="Image ml183fu108.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.8 ± 0.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">151 ± 12.7</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412128</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu109.jpg" alt="Image ml183fu109.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.0 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.3 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412129</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu110.jpg" alt="Image ml183fu110.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412130</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu111.jpg" alt="Image ml183fu111.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.4 ± 0.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.8 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390868.0002</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu112.jpg" alt="Image ml183fu112.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.0 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.8 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0391033</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu113.jpg" alt="Image ml183fu113.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.4 ± 0.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.8 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412150</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu114.jpg" alt="Image ml183fu114.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.0 ± 0.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">17.6 ± 0.4</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412151</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu115.jpg" alt="Image ml183fu115.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.2 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.0 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412152</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu116.jpg" alt="Image ml183fu116.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.3 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.1 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412153</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu117.jpg" alt="Image ml183fu117.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.1 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10.9 ± 2.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412154</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu118.jpg" alt="Image ml183fu118.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.3 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.9 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412155</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu119.jpg" alt="Image ml183fu119.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.7 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.5 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412156</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu120.jpg" alt="Image ml183fu120.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12.3 ± 0.9</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.5 ± 0.4</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>BIM-0206969</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu121.jpg" alt="Image ml183fu121.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390869.0002 see pg 2</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu122.jpg" alt="Image ml183fu122.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.9 ± 0.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.8 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412157</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu123.jpg" alt="Image ml183fu123.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">48.1 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">158.1 ± 2.8</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412158</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu124.jpg" alt="Image ml183fu124.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">38.7 ± 4.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412159</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu125.jpg" alt="Image ml183fu125.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412160</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu126.jpg" alt="Image ml183fu126.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412161</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu127.jpg" alt="Image ml183fu127.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412162</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu128.jpg" alt="Image ml183fu128.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">59.0 ± 1.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.6 ± 0.2</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412167</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu129.jpg" alt="Image ml183fu129.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.4 ± 0.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.3 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412168</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu130.jpg" alt="Image ml183fu130.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.9 ± 0.6</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">77.0 ± 1.4</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412169</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu131.jpg" alt="Image ml183fu131.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.7 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25.2 ± 3.0</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412177</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu132.jpg" alt="Image ml183fu132.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10.3 ± 1.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">~ 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412178</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu133.jpg" alt="Image ml183fu133.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.5 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.50 ± 0.02</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412179</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu134.jpg" alt="Image ml183fu134.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.7 ± 0.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.4 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412180</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu135.jpg" alt="Image ml183fu135.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.1 ± 1.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>BIM-0207006</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu136.jpg" alt="Image ml183fu136.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.89 ± 0.04</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.7 ± 1.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412181</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu137.jpg" alt="Image ml183fu137.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">73.8 ± 9.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">38.9 ± 6.9</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>BIM-0207011</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu138.jpg" alt="Image ml183fu138.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.8 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.3 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>BIM-0207090</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu139.jpg" alt="Image ml183fu139.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.9 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">79.0 ± 3.9</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412193</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu140.jpg" alt="Image ml183fu140.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">27.3 ± 0.8</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">79.4 ± 3.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412197</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu141.jpg" alt="Image ml183fu141.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.4 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.0 ± 0.2</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412198</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu142.jpg" alt="Image ml183fu142.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.1 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412199</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu143.jpg" alt="Image ml183fu143.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11.8 ± 0.4</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">153.1 ± 23.8</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412200</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu144.jpg" alt="Image ml183fu144.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">157.8 ± 7.0</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0412201</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu145.jpg" alt="Image ml183fu145.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">91.5 ± 7.4</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425206</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu146.jpg" alt="Image ml183fu146.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.3 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.9 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425207</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu147.jpg" alt="Image ml183fu147.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.0 ± 0.7</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.0 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425208</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu148.jpg" alt="Image ml183fu148.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">43.5 ± 8.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">144.6 ± 5.7</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425209</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu149.jpg" alt="Image ml183fu149.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.0 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">55.0 ± 3.9</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425210</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu150.jpg" alt="Image ml183fu150.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.5 ± 0.2</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">29.0 ± 1.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425211</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu151.jpg" alt="Image ml183fu151.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">13.5 ± 1.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">182.0 ± 10.9</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425212</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu152.jpg" alt="Image ml183fu152.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26.8 ± 2.9</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425213</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu153.jpg" alt="Image ml183fu153.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.6 ± 2.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.3 ± 0.1</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425214</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu154.jpg" alt="Image ml183fu154.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.0 ± 0.4</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">~ 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425614</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu155.jpg" alt="Image ml183fu155.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.4 ± 0.6</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425640</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu156.jpg" alt="Image ml183fu156.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425641</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu157.jpg" alt="Image ml183fu157.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.0 ± 0.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425683</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu158.jpg" alt="Image ml183fu158.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.0 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0425710</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu159.jpg" alt="Image ml183fu159.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20.0 ± 0.5</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0435806</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu160.jpg" alt="Image ml183fu160.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">30.0 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 100</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0437258</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu161.jpg" alt="Image ml183fu161.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.1 ± 0.3</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.0 ± 0.4</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>MLS-0390969.0003</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu162.jpg" alt="Image ml183fu162.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.6 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.8 ± 0.3</td></tr><tr><td headers="hd_h_ml183.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>BIM-0633392</b></td><td headers="hd_h_ml183.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK55068/bin/ml183fu163.jpg" alt="Image ml183fu163.jpg" /></div></td><td headers="hd_h_ml183.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.3 ± 0.1</td><td headers="hd_h_ml183.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.20 ± 0.00</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
|
|
|
|
|
|
|
|
|
|
<!-- Book content -->
|
|
|
|
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js"> </script>
|
|
|
|
|
|
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal107 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
|
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
|
|
|
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3968615.js" snapshot="books"></script></body>
|
|
</html>
|