Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432

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Humphreys, Philip G. and Anderson, Niall A. and Bamborough, Paul and Baxter, Andrew and Chung, Chun-wa and Cookson, Rosa and Craggs, Peter D. and Dalton, Toryn and Fournier, Julie C. L. and Gordon, Laurie J. and Gray, Heather F. and Gray, Matthew W. and Gregory, Richard and Hirst, David J. and Jamieson, Craig and Jones, Katherine L. and Kessedjian, Hripsimee and Lugo, David and McGonagle, Grant and Patel, Vipulkumar K. and Patten, Christopher and Poole, Darren L. and Prinjha, Rab K. and Ramirez-Molina, Cesar and Rioja, Inmaculada and Seal, Gail and Stafford, Kayleigh A. J. and Shah, Rishi R. and Tape, Daniel and Theodoulou, Natalie H. and Tomlinson, Laura R. and Ukuser, Sabri and Wall, Ian D. and Wellaway, Natalie and White, Gemma (2022) Identification and optimization of a ligand-efficient benzoazepinone bromodomain and extra terminal (BET) family acetyl-lysine mimetic into the oral candidate quality molecule I-BET432. Journal of Medicinal Chemistry, 65 (22). pp. 15174-15207. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.2c01102)

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Abstract

The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein–protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure–activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.

ORCID iDs

Humphreys, Philip G., Anderson, Niall A., Bamborough, Paul, Baxter, Andrew, Chung, Chun-wa, Cookson, Rosa, Craggs, Peter D., Dalton, Toryn, Fournier, Julie C. L., Gordon, Laurie J., Gray, Heather F., Gray, Matthew W., Gregory, Richard, Hirst, David J., Jamieson, Craig ORCID logoORCID: https://orcid.org/0000-0002-6567-8272, Jones, Katherine L., Kessedjian, Hripsimee, Lugo, David, McGonagle, Grant, Patel, Vipulkumar K., Patten, Christopher, Poole, Darren L., Prinjha, Rab K., Ramirez-Molina, Cesar, Rioja, Inmaculada, Seal, Gail, Stafford, Kayleigh A. J., Shah, Rishi R., Tape, Daniel, Theodoulou, Natalie H., Tomlinson, Laura R., Ukuser, Sabri, Wall, Ian D., Wellaway, Natalie and White, Gemma;
  • Item type:Article
    ID code:83588
    Dates:
    Date
    Event
    24 November 2022
    Published
    15 November 2022
    Published Online
    15 November 2022
    Accepted
    Notes:Copyright © 2022 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.2c01102.
    Subjects:Medicine > Pharmacy and materia medica > Pharmaceutical chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:20 Dec 2022 16:37
    Last modified:16 Dec 2024 02:37
    URI:https://strathprints.strath.ac.uk/id/eprint/83588
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