The optimization of potent ATAD2 and CECR2 bromodomain inhibitors with an atypical binding mode

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Lucas, Simon C. C. and Atkinson, Stephen J. and Bamborough, Paul and Barnett, Heather and Chung, Chun-wa and Gordon, Laurie and Mitchell, Darren J. and Phillipou, Alexander and Prinjah, Rab K. and Sheppard, Robert J. and Tomkinson, Nicholas C. O. and Watson, Robert J. and Demont, Emmanuel H. (2020) The optimization of potent ATAD2 and CECR2 bromodomain inhibitors with an atypical binding mode. Journal of Medicinal Chemistry, 63 (10). pp. 5212-5241. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.0c00021)

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Abstract

Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.

ORCID iDs

Lucas, Simon C. C. ORCID logoORCID: https://orcid.org/0000-0003-0636-7164, Atkinson, Stephen J., Bamborough, Paul, Barnett, Heather, Chung, Chun-wa, Gordon, Laurie, Mitchell, Darren J., Phillipou, Alexander, Prinjah, Rab K., Sheppard, Robert J., Tomkinson, Nicholas C. O. ORCID logoORCID: https://orcid.org/0000-0002-5509-0133, Watson, Robert J. and Demont, Emmanuel H.;
  • Item type:Article
    ID code:73265
    Dates:
    Date
    Event
    28 May 2020
    Published
    22 April 2020
    Published Online
    4 April 2020
    Accepted
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:21 Jul 2020 15:02
    Last modified:11 Nov 2024 12:46
    URI:https://strathprints.strath.ac.uk/id/eprint/73265
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