Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity
Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large comme...
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-01, Vol.65 (1), p.562-578 |
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| creator | Steadman, David Atkinson, Benjamin N Zhao, Yuguang Willis, Nicky J Frew, Sarah Monaghan, Amy Patel, Chandni Armstrong, Emma Costelloe, Kathryn Magno, Lorenza Bictash, Magda Jones, E. Yvonne Fish, Paul V Svensson, Fredrik |
| description | Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC50 < 500 nM. A critical selection process was then applied with two clusters and two singletons (1–4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/β-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures. |
| doi_str_mv | 10.1021/acs.jmedchem.1c01735 |
| format | Article |
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Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/β-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. 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Yvonne</creatorcontrib><creatorcontrib>Fish, Paul V</creatorcontrib><creatorcontrib>Svensson, Fredrik</creatorcontrib><title>Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC50 < 500 nM. A critical selection process was then applied with two clusters and two singletons (1–4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/β-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.</description><subject>Animals</subject><subject>beta Catenin - drug effects</subject><subject>Binding Sites</subject><subject>Carboxylic Ester Hydrolases - antagonists & inhibitors</subject><subject>Crystallography, X-Ray</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Esterases - antagonists & inhibitors</subject><subject>High-Throughput Screening Assays</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Molecular</subject><subject>Molecular Docking Simulation</subject><subject>Protein Binding</subject><subject>Structure-Activity Relationship</subject><subject>Wnt Signaling Pathway - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EouXxBwh5ySZl_GjSLKtCoVJVFjy2keNMqFESF9uhlK8n0JYlq5Fm7r0zcwi5YDBgwNm10n7wVmOhl1gPmAaWiOEB6bMhh0iOQB6SPgDnEY-56JET798AQDAujklPyFSkySjtk_bFuNCqij5qh9iY5pXeGIc6VBs6K7AJpjTo6QLXdOrUa911okfzhQWdNUuTm2Cdp7akE-Vy-7mp0Ad0yiNd2NDWdG3Cki5UY2tbKUfHOpgPEzZn5KhUlcfzXT0lz9Pbp8l9NH-4m03G80iJVIYoLbiQMil4onAkUpA4BJnHJUOtpSo4KyDhskAeS6Zj0DmCQKHkMEbJQSfilFxtc1fOvrfdbVltvMaqUg3a1mc8ZoKngou4k8qtVDvrvcMyWzlTK7fJGGQ_wLMOeLYHnu2Ad7bL3YY272Z_pj3hTgBbwa_dtq7pHv4_8xsgdZGw</recordid><startdate>20220113</startdate><enddate>20220113</enddate><creator>Steadman, David</creator><creator>Atkinson, Benjamin N</creator><creator>Zhao, Yuguang</creator><creator>Willis, Nicky J</creator><creator>Frew, Sarah</creator><creator>Monaghan, Amy</creator><creator>Patel, Chandni</creator><creator>Armstrong, Emma</creator><creator>Costelloe, Kathryn</creator><creator>Magno, Lorenza</creator><creator>Bictash, Magda</creator><creator>Jones, E. 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| ispartof | Journal of medicinal chemistry, 2022-01, Vol.65 (1), p.562-578 |
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| subjects | Animals beta Catenin - drug effects Binding Sites Carboxylic Ester Hydrolases - antagonists & inhibitors Crystallography, X-Ray Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Esterases - antagonists & inhibitors High-Throughput Screening Assays Male Mice Mice, Inbred C57BL Models, Molecular Molecular Docking Simulation Protein Binding Structure-Activity Relationship Wnt Signaling Pathway - drug effects |
| title | Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity |
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