CINXE.COM

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name="baidu-site-verification" content="bMqlqGgPRi" /> <title>Developing Chemical Probes for Epigenetic Targets | Tocris Bioscience</title> <meta name="description" content="The leading supplier of novel and exclusive research tools including GPCR ligands, neurotransmitters, ion channel modulators and signaling inhibitors." /> <script id="json-ld" type="application/ld+json">[{"@context":"https://schema.org/","@type":"Blog","name":"Developing Chemical Probes for Epigenetic Targets","description":"The leading supplier of novel and exclusive research tools including GPCR ligands, neurotransmitters, ion channel modulators and signaling inhibitors.","dateCreated":"2018/04/13","url":"https://www.tocris.com/resources/tocris-blog/developing-chemical-probes-epigenetic-targets","keywords":"","text":"\r\n\r\nThe Structural Genomics Consortium (SGC) was set-up in 2004, with the goal of solving the protein structures of relevance to human disease. Since then the mission has expanded to advancing drug discovery via open access sharing of resources and knowledge. Initially, the SGC had two sites, at the University of Toronto (Canada) and Oxford University (UK). It has now added sites at the Karolinska Institute (Sweden), the University of North Carolina at Chapel Hill (USA), Frankfurt University (Germany), Unicamp (Brazil) and the Montreal Neurological Institute (McGill University, Canada). To achieve its scientific goals, the SGC collaborates openly with nine pharmaceutical companies and hundreds of academics at universities around the world. All of the research output is shared with no intellectual property restrictions.\r\n\r\nIn 2009, building on our strengths in structural biology, the SGC launched a program to create small molecule inhibitors and antagonists, named chemical probes, targeting epigenetic proteins. Structural biology is a key component to all SGC programs focused on developing chemical probes. For example, at the start of the epigenetic chemical probe program, the SGC had ~44 crystal structures of bromodomains, methyltransferases, and methyl lysine readers. To date, the SGC has over 400 structures in these protein families and close to 2100 structures in total. Further, the SGC has established different avenues to share these data, Chromohub and Target Enabling Packages.\r\n\r\nChemical probe development: The chemical probes are developed in an iterative process of in vitro screening, binding confirmation and medicinal chemistry optimization until hits with < 100 nM potency are identified. The iterative process includes single-point concentration screening, confirmation with dose-response, structure-activity relationship (SAR), and initial selectivity testing. This is followed up with an assessment of the potency in cells (and/or target engagement). Hits rarely meet the cellular potency criteria at the first attempt. In vitro screening and medicinal chemistry optimization continue until more potent hits that meet the criteria for cellular activity are developed. The SGC defines a chemical probe as being a small molecule that meets the following criteria:\r\n\r\n\r\n\tIC50 or Kd < 100 nM in vitro\r\n\t> 30-fold selectivity over proteins in the same family\r\n\tSignificant on-target cellular activity at 1 \u03bcM\r\n\r\n\r\nIn order to minimize unexpected off-target effects, the SGC also strives to find a chemotype-matched negative control for each chemical probe. The control is subjected to the same rigorous in vitro selectivity and cellular activity assessment as the chemical probe. Both the probe and its control are screened for selectivity against 119 membrane receptors, ion channels and kinases via the Psychoactive Drug Screen Program (PDSP) at the University of North Carolina and Eurofins.\r\n\r\nEach chemical probe is the result of a truly open collaboration with medicinal chemists within the SGC\u2019s pharmaceutical company partners or with academic researchers who have agreed to make the molecules freely available to the research community. To date, the SGC chemical probes program has resulted in over 40 selective chemical probes that antagonize or inhibit specific domains in epigenetic targets: www.thesgc.org/chemical-probes.\r\n\r\nThe SGC has successfully delivered chemical probes for proteins that modify ((de-)methylate, acetylate) or bind (at methyl/acetyllysine) histones H3 and H4. Of note, the lysine methyltransferase antagonists for WDR5 and EED are of considerable interest to the research community because they ultimately inhibit (via an allosteric mechanism) MLL1 (which writes the H3K4me3 mark) and PRC2 (which writes the H3K27me3), respectively. PRC2 is a great example of where methyltransferase inhibition may be effected directly (via EZH2/H1) or allosterically (via EED). The use of orthogonal probes (either by chemotype or mode of action) to modulate a protein target allows a more comprehensive understanding of the underlying biology and resulting phenotype. This also enables additional control experiments that complement the use of a (negative) control compound. In addition to the histone-targeting methyltransferases, the SGC has also developed chemical probes for methyltransferases whose main substrate is a cytosolic (i.e. non-histone) target. These include SMYD2, SMYD3, and PRMT4.\r\n\r\nSharing chemical probes: The SGC shares small aliquots of each chemical probe with researchers using a \u2018trust agreement\u2019 rather than a \u2018material transfer agreement\u2019. In this arrangement, recipients of the samples agree to become trustees of the material and must use it to further the public good by placing their research findings in the public domain without intellectual property restrictions (www.thesgc.org/click-trust/faqs). In addition, the SGC works closely with commercial partners such as Tocris, to make the latest chemical probes readily available to researchers.\r\n\r\nImpact: It is evident from the literature that more easily \u2018druggable\u2019 epigenetic targets have now been furnished with chemical probes. These probes are invaluable for furthering researchers\u2019 understanding of the role(s) of their target in various biological models. SGC chemical probes have also been useful from a translational perspective. Analogs of chemical probes for BET, EZH2, DOT1L, LSD1, and PRMT5 are currently in clinical trials.\r\n"},{"@context":"http://schema.org","@type":"WebPage","breadcrumb":{"@context":"http://schema.org","@type":"BreadcrumbList","itemListElement":[{"@context":"http://schema.org","@type":"ListItem","position":1,"item":{"@context":"http://schema.org","@type":"Thing","@id":"https://www.tocris.com/","name":"Home"}},{"@context":"http://schema.org","@type":"ListItem","position":2,"item":{"@context":"http://schema.org","@type":"Thing","@id":"https://www.tocris.com/resources","name":"Resources"}},{"@context":"http://schema.org","@type":"ListItem","position":3,"item":{"@context":"http://schema.org","@type":"Thing","@id":"https://www.tocris.com/resources/tocris-blog","name":"Tocris Blog"}}]},"potentialaction":{"query":""}}]</script> <meta name="generator" content="Drupal 7 (https://www.drupal.org)" /> <link rel="shortlink" href="https://www.tocris.com/node/1066" /> <meta property="og:site_name" 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class="region region-content"> <section id="block-system-main" class="block block-system clearfix"> <div> <div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even" property="content:encoded"><div class="blog-image-border"><img alt="Developing Chemical Probes for Epigenetic Targets" itemprop="image" src="https://resources.tocris.com/images/blog/banners/chemical-probes-for-epigenetic-targets.jpg" title="Developing Chemical Probes for Epigenetic Targets" /></div> <p>The Structural Genomics Consortium (SGC) was set-up in 2004, with the goal of solving the protein structures of relevance to human disease. Since then the mission has expanded to advancing drug discovery via open access sharing of resources and knowledge. Initially, the SGC had two sites, at the University of Toronto (Canada) and Oxford University (UK). It has now added sites at the Karolinska Institute (Sweden), the University of North Carolina at Chapel Hill (USA), Frankfurt University (Germany), Unicamp (Brazil) and the Montreal Neurological Institute (McGill University, Canada). To achieve its scientific goals, the SGC collaborates openly with nine pharmaceutical companies and hundreds of academics at universities around the world. All of the research output is shared with no intellectual property restrictions.</p> <p>In 2009, building on our strengths in structural biology, the SGC launched a program to create small molecule inhibitors and antagonists, named chemical probes, targeting <a href="/cell-biology/epigenetics" target="_blank">epigenetic proteins</a>. Structural biology is a key component to all SGC programs focused on developing chemical probes. For example, at the start of the epigenetic chemical probe program, the SGC had ~44 crystal structures of bromodomains, methyltransferases, and methyl lysine readers. To date, the SGC has over 400 structures in these protein families and close to 2100 structures in total. Further, the SGC has established different avenues to share these data, Chromohub and Target Enabling Packages.</p> <p><strong>Chemical probe development:</strong> The chemical probes are developed in an iterative process of <em>in vitro</em> screening, binding confirmation and medicinal chemistry optimization until hits with < 100 nM potency are identified. The iterative process includes single-point concentration screening, confirmation with dose-response, structure-activity relationship (SAR), and initial selectivity testing. This is followed up with an assessment of the potency in cells (and/or target engagement). Hits rarely meet the cellular potency criteria at the first attempt. <em>In vitro</em> screening and medicinal chemistry optimization continue until more potent hits that meet the criteria for cellular activity are developed. The SGC defines a chemical probe as being a small molecule that meets the following criteria:</p> <ul> <li>IC<sub>50</sub> or K<sub>d</sub> < 100 nM <em>in vitro</em></li> <li>> 30-fold selectivity over proteins in the same family</li> <li>Significant on-target cellular activity at 1 μM</li> </ul> <p>In order to minimize unexpected off-target effects, the SGC also strives to find a chemotype-matched negative control for each chemical probe. The control is subjected to the same rigorous <em>in vitro</em> selectivity and cellular activity assessment as the chemical probe. Both the probe and its control are screened for selectivity against 119 membrane receptors, ion channels and kinases via the Psychoactive Drug Screen Program (PDSP) at the <a href="https://pdspdb.unc.edu/pdspWeb/" rel="no follow" target="_blank">University of North Carolina</a> and <a href="https://www.eurofinsdiscovery.com" rel="no follow" target="_blank">Eurofins</a>.</p> <p>Each chemical probe is the result of a truly open collaboration with medicinal chemists within the SGC’s pharmaceutical company partners or with academic researchers who have agreed to make the molecules freely available to the research community. To date, the SGC chemical probes program has resulted in over 40 selective chemical probes that antagonize or inhibit specific domains in epigenetic targets: <a href="https://www.thesgc.org/chemical-probes" rel="no follow" target="_blank">www.thesgc.org/chemical-probes</a>.</p> <p>The SGC has successfully delivered chemical probes for proteins that modify ((de-)methylate, acetylate) or bind (at methyl/acetyllysine) histones H3 and H4. Of note, the lysine methyltransferase antagonists for <a href="/pharmacology/wdr5" target="_blank">WDR5</a> and EED are of considerable interest to the research community because they ultimately inhibit (via an allosteric mechanism) <a href="/pharmacology/wdr5" target="_blank">MLL1</a> (which writes the H3K4me3 mark) and PRC2 (which writes the H3K27me3), respectively. <a href="/pharmacology/ezh2" target="_blank">PRC2</a> is a great example of where methyltransferase inhibition may be effected directly (via EZH2/H1) or allosterically (via EED). The use of orthogonal probes (either by chemotype or mode of action) to modulate a protein target allows a more comprehensive understanding of the underlying biology and resulting phenotype. This also enables additional control experiments that complement the use of a (negative) control compound. In addition to the histone-targeting methyltransferases, the SGC has also developed chemical probes for methyltransferases whose main substrate is a cytosolic (i.e. non-histone) target. These include <a href="/pharmacology/other-lysine-methyltransferases" target="_blank"> SMYD2</a>, <a href="/pharmacology/other-lysine-methyltransferases" target="_blank"> SMYD3</a>, and <a href="/pharmacology/protein-arginine-methyltransferases" target="_blank">PRMT4</a>.</p> <p><strong>Sharing chemical probes:</strong> The SGC shares small aliquots of each chemical probe with researchers using a ‘trust agreement’ rather than a ‘material transfer agreement’. In this arrangement, recipients of the samples agree to become trustees of the material and must use it to further the public good by placing their research findings in the public domain without intellectual property restrictions (<a href="https://www.thesgc.org/click-trust/faqs" rel="nofollow" target="_blank">www.thesgc.org/click-trust/faqs</a>). In addition, the SGC works closely with commercial partners such as Tocris, to make the latest chemical probes readily available to researchers.</p> <p><strong>Impact:</strong> It is evident from the literature that more easily ‘druggable’ epigenetic targets have now been furnished with chemical probes. These probes are invaluable for furthering researchers’ understanding of the role(s) of their target in various biological models. SGC chemical probes have also been useful from a translational perspective. Analogs of chemical probes for BET, EZH2, DOT1L, LSD1, and PRMT5 are currently in clinical trials.</p> </div></div></div><div class="field field-name-field-blog-categories field-type-taxonomy-term-reference field-label-above"><div class="field-label">Blog Categories: </div><div class="field-items"><div class="field-item even"><a href="/resources/tocris-blog/blog-categories/epigenetics" typeof="skos:Concept" property="rdfs:label skos:prefLabel">Epigenetics</a></div></div></div><div class="field field-name-field-tags field-type-taxonomy-term-reference field-label-above"><div class="field-label">Tags: </div><div class="field-items"><div class="field-item even"><a href="/resources/tocris-blog/tags/epigenetics" typeof="skos:Concept" property="rdfs:label skos:prefLabel">Epigenetics</a></div><div class="field-item odd"><a href="/resources/tocris-blog/tags/chemical-probes" typeof="skos:Concept" property="rdfs:label skos:prefLabel">Chemical Probes</a></div><div class="field-item even"><a 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