2. Academic Validation
  3. A Chemical Probe for the ATAD2 Bromodomain

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

Affiliations

  • 1 GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK. Paul.A.Bamborough@gsk.com.
  • 2 GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
  • 3 GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK. Emmanuel.H.Demont@gsk.com.
  • 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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