A Chemical Probe for the ATAD2 Bromodomain

  • Angew Chem Int Ed Engl. 2016 Sep 12;55(38):11382-6. doi: 10.1002/anie.201603928.
Paul Bamborough  1 ,  Chun-Wa Chung  2 ,  Emmanuel H Demont  3 ,  Rebecca C Furze  2 ,  Andrew J Bannister  4 ,  Ka Hing Che  4 ,  Hawa Diallo  2 ,  Clement Douault  2 ,  Paola Grandi  5 ,  Tony Kouzarides  4 ,  Anne-Marie Michon  5 ,  Darren J Mitchell  2 ,  Rab K Prinjha  2 ,  Christina Rau  5 ,  Samuel Robson  4 ,  Robert J Sheppard  2  6 ,  Richard Upton  2 ,  Robert J Watson  2
Affiliations
  • 1. GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK. [email protected].
  • 2. GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
  • 3. GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK. [email protected].
  • 4. Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QN, UK.
  • 5. Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, 69117, Heidelberg, Germany.
  • 6. AstraZeneca, Milton Road, Cambridge, CB4 OWG, UK.
PMID: 27530368 DOI: 10.1002/anie.201603928
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.

Keywords
bioisosteres; conformation analysis; epigenetics; fluorine; medicinal chemistry.
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