GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain

  • ACS Med Chem Lett. 2016 May 9;7(6):552-7. doi: 10.1021/acsmedchemlett.6b00092.
Paul Bamborough  1 ,  Heather A Barnett  1 ,  Isabelle Becher  2 ,  Mark J Bird  1 ,  Chun-Wa Chung  1 ,  Peter D Craggs  1 ,  Emmanuel H Demont  1 ,  Hawa Diallo  1 ,  David J Fallon  3 ,  Laurie J Gordon  1 ,  Paola Grandi  2 ,  Clare I Hobbs  1 ,  Edward Hooper-Greenhill  1 ,  Emma J Jones  1 ,  Robert P Law  3 ,  Armelle Le Gall  1 ,  David Lugo  1 ,  Anne-Marie Michon  2 ,  Darren J Mitchell  1 ,  Rab K Prinjha  1 ,  Robert J Sheppard  1 ,  Allan J B Watson  4 ,  Robert J Watson  1
Affiliations
  • 1. Epinova Discovery Performance Unit, Quantitative Pharmacology, Experimental Medicine Unit, Flexible Discovery Unit, and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
  • 2. Cellzome GmbH, GlaxoSmithKline , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
  • 3. Epinova Discovery Performance Unit, Quantitative Pharmacology, Experimental Medicine Unit, Flexible Discovery Unit, and Platform Technology and Science, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.; WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
  • 4. WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
PMID: 27326325 DOI: 10.1021/acsmedchemlett.6b00092
Abstract

The BRPF (Bromodomain and PHD Finger-containing) protein family are important scaffolding proteins for assembly of MYST Histone Acetyltransferase complexes. A selective benzimidazolone BRPF1 Inhibitor showing micromolar activity in a cellular target engagement assay was recently described. Herein, we report the optimization of this series leading to the identification of a superior BRPF1 Inhibitor suitable for in vivo studies.

Keywords
BET; BRD1; BRPF1; BRPF2; BRPF3; bromodomain; chemical probe; epigenetics; inhibitor.
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