Structure-Based Discovery and Optimization of Furo[3,2-<i>c</i>]pyridin-4(5<i>H</i>)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.

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dc.contributor.author Li, Junhua
dc.contributor.author Zhang, Cheng
dc.contributor.author Xu, Hongrui
dc.contributor.author Wang, Chao
dc.contributor.author Dong, Ruibo
dc.contributor.author Shen, Hui
dc.contributor.author Zhuang, Xiaoxi
dc.contributor.author Chen, Xiaoshan
dc.contributor.author Li, Qiu
dc.contributor.author Lu, Jibu
dc.contributor.author Zhang, Maofeng
dc.contributor.author Wu, Xishan
dc.contributor.author Loomes, Kerry M
dc.contributor.author Zhou, Yulai
dc.contributor.author Zhang, Yan
dc.contributor.author Liu, Jinsong
dc.contributor.author Xu, Yong
dc.coverage.spatial United States
dc.date.accessioned 2022-06-10T04:37:04Z
dc.date.available 2022-06-10T04:37:04Z
dc.date.issued 2022-04
dc.identifier.citation (2022). Journal of Medicinal Chemistry, 65(7), 5760-5799.
dc.identifier.issn 0022-2623
dc.identifier.uri https://hdl.handle.net/2292/59723
dc.description.abstract Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-<i>c</i>]pyridin-4(5<i>H</i>)-one derivatives as novel BD2-selective BET inhibitors. The representative compound <b>8l</b> (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC<sub>50</sub>) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, <b>8l</b> exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound <b>8l</b> displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC<sub>50</sub> = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. <b>8l</b> also demonstrated good metabolic stability in vitro. These data indicate that <b>8l</b> may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).
dc.format.medium Print-Electronic
dc.language eng
dc.publisher American Chemical Society (ACS)
dc.relation.ispartofseries Journal of medicinal chemistry
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm
dc.subject Cell Line, Tumor
dc.subject Cell Cycle Proteins
dc.subject Nuclear Proteins
dc.subject Transcription Factors
dc.subject Antineoplastic Agents
dc.subject Protein Domains
dc.subject Hematology
dc.subject Orphan Drug
dc.subject Cancer
dc.subject Rare Diseases
dc.subject 5.1 Pharmaceuticals
dc.subject 0304 Medicinal and Biomolecular Chemistry
dc.subject 0305 Organic Chemistry
dc.subject 1115 Pharmacology and Pharmaceutical Sciences
dc.title Structure-Based Discovery and Optimization of Furo[3,2-<i>c</i>]pyridin-4(5<i>H</i>)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.
dc.type Journal Article
dc.identifier.doi 10.1021/acs.jmedchem.2c00100
pubs.issue 7
pubs.begin-page 5760
pubs.volume 65
dc.date.updated 2022-05-02T05:55:13Z
dc.rights.holder Copyright: The author en
dc.identifier.pmid 35333526 (pubmed)
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/35333526
pubs.end-page 5799
pubs.publication-status Published
dc.rights.accessrights http://purl.org/eprint/accessRights/RetrictedAccess en
pubs.subtype Journal Article
pubs.elements-id 891822
pubs.org-id Science
pubs.org-id Biological Sciences
pubs.org-id Science Research
pubs.org-id Maurice Wilkins Centre (2010-2014)
dc.identifier.eissn 1520-4804
pubs.record-created-at-source-date 2022-05-02
pubs.online-publication-date 2022-03-25


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