{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:08:13Z","timestamp":1790096893625,"version":"4.0.1"},"reference-count":73,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/PR7222\/MED\/31\/1901\/2012"],"award-info":[{"award-number":["BT\/PR7222\/MED\/31\/1901\/2012"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>BRD4, a member of the bromodomain and extra-terminal (BET) family of epigenetic readers, plays a central role in transcriptional regulation and is implicated in a wide spectrum of diseases. Although BRD4 inhibitors targeting both bromodomains have advanced into clinical studies, their development and therapeutic use are limited by dose-limiting toxicities associated with nonselective BET inhibition. These limitations underscore the need for domain-selective targeting strategies. In this study, we performed fragment-based screening of a 200-compound diversity library against BRD4-BD2, identifying three chemically distinct hits: CCBT-T-226 (methyl 2-(2-(3,5-dimethylisoxazol-4-yl)acetamido)-5-propylthiazole-4-carboxylate), CCBT-F-70 (2-(benzylamino)pyrimidin-4(3H)-one), and CCBT-F-182 (3-(8-methyl-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl)aniline). These fragments were validated as binders using TSA, ITC, STD-NMR, and 1H-15N HSQC NMR. Among them, CCBT-T-226 and CCBT-F-182 exhibited measurable BD2-over-BD1 selectivity, with CCBT-F-182 showing a pronounced domain preference, and CCBT-T-226 demonstrating approximately 7-fold selectivity for BD2 over BD1. X-ray crystallography of the BRD4-BD2\u2013CCBT-F-70 complex, together with cofolding models for CCBT-T-226 and CCBT-F-182, provides a structural framework for the rational, structure-guided development of potent and selective BRD4-BD2 inhibitors.<\/jats:p>","DOI":"10.1021\/acsomega.6c06516","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:02:08Z","timestamp":1789002128000},"page":"56159-56169","source":"Crossref","is-referenced-by-count":0,"title":["Fragment-Based\nDiscovery of BRD4-BD2 Selective Binders:\nBiophysical Validation and Structural Insights for Domain-Selective\nInhibitor Design"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0112-2022","authenticated-orcid":true,"given":"Sriram Prakash","family":"Baskaran","sequence":"first","affiliation":[{"name":"Centre for Chemical Biology and Therapeutics, Institute for Stem Cell Science and Regenerative Medicine , GKVK \u2212 Post, Bellary Road , ,","place":["Bengaluru, India, 560 065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2005-0892","authenticated-orcid":true,"given":"Yashini Vidhya","family":"Subramani","sequence":"additional","affiliation":[{"name":"Centre for Chemical Biology and Therapeutics, Institute for Stem Cell Science and Regenerative Medicine , GKVK \u2212 Post, Bellary Road , ,","place":["Bengaluru, India, 560 065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sneha G.","family":"Bairy","sequence":"additional","affiliation":[{"name":"Centre for Chemical Biology and Therapeutics, Institute for Stem Cell Science and Regenerative Medicine , GKVK \u2212 Post, Bellary Road , ,","place":["Bengaluru, India, 560 065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0524-8000","authenticated-orcid":true,"given":"Thazhe Kootteri","family":"Prasad","sequence":"additional","affiliation":[{"name":"Centre for Chemical Biology and Therapeutics, Institute for Stem Cell Science and Regenerative Medicine , GKVK \u2212 Post, Bellary Road , ,","place":["Bengaluru, India, 560 065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikrant","family":"Kumar","sequence":"additional","affiliation":[{"name":"Centre for Chemical Biology and Therapeutics, Institute for Stem Cell Science and Regenerative Medicine , GKVK \u2212 Post, Bellary Road , ,","place":["Bengaluru, India, 560 065"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Sridhar","sequence":"additional","affiliation":[{"name":"National Institute of Mental Health and Neurosciences (NIMHANS) , , Hosur Main Road , ,","place":["Bengaluru, India, 560 029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balasundaram","family":"Padmanabhan","sequence":"additional","affiliation":[{"name":"National Institute of Mental Health and Neurosciences (NIMHANS) , , Hosur Main Road , ,","place":["Bengaluru, India, 560 029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7511-7161","authenticated-orcid":true,"given":"Neelagandan","family":"Kamariah","sequence":"additional","affiliation":[{"name":"Centre for Chemical Biology and Therapeutics, Institute for Stem Cell Science and Regenerative Medicine , GKVK \u2212 Post, Bellary Road , ,","place":["Bengaluru, India, 560 065"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"issue":"8","key":"2026092211040354300_cit1","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/nrg.2016.59","article-title":"The Molecular Hallmarks of Epigenetic Control","volume":"17","author":"Allis","year":"2016","journal-title":"Nat. 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