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

Simon C. C. Lucas, Stephen J. Atkinson, Paul Bamborough, Heather Barnett, Chun-wa Chung, Laurie Gordon, Darren J. Mitchell, Alexander Phillipou, Rab K. Prinjah, Robert J. Sheppard, Nicholas C. O. Tomkinson, Robert J. Watson, Emmanuel H. Demont

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)5212-5241
Number of pages30
JournalJournal of Medicinal Chemistry
Volume63
Issue number10
Early online date22 Apr 2020
DOIs
Publication statusPublished - 28 May 2020

Keywords

  • anions
  • substituents
  • inhibitors
  • sulfones
  • selectivity
  • ATAD2
  • CECR2

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