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

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

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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.