A chemical probe for the ATAD2 bromodomain

Paul Bamborough, Chun-wa Chung, Emmanuel H. Demont, Rebecca C. Furze, Andrew J. Bannister, Ka Hing Che, Hawa Diallo, Clement Douault, Paola Grandi, Tony Kouzarides, Anne-Marie Michon, Darren J. Mitchell, Rab K. Prinjha, Christina Rau, Samuel Robson, Robert J. Sheppard, Richard Upton, Robert J. Watson

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Abstract

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.
Original languageEnglish
Pages (from-to)11382-11386
Number of pages5
JournalAngewandte Chemie International Edition
Volume55
Issue number38
Early online date17 Aug 2016
DOIs
Publication statusPublished - 12 Sep 2016
Externally publishedYes

Keywords

  • RCUK
  • BBSRC
  • RG69031

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