GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain

Paul Bamborough; Heather A Barnett; Isabelle Becher; Mark J Bird; Chun-Wa Chung; Peter D Craggs; Emmanuel H Demont; Hawa Diallo; David J Fallon; Laurie J Gordon; Paola Grandi; Clare I Hobbs; Edward Hooper-Greenhill; Emma J Jones; Robert P Law; Armelle Le Gall; David Lugo; Anne-Marie Michon; Darren J Mitchell; Rab K Prinjha; Robert J Sheppard; Allan J B Watson; Robert J Watson

doi:10.1021/acsmedchemlett.6b00092

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. eCollection 2016 Jun 9.

Authors

Paul Bamborough¹, Heather A Barnett¹, Isabelle Becher², Mark J Bird¹, Chun-Wa Chung¹, Peter D Craggs¹, Emmanuel H Demont¹, Hawa Diallo¹, David J Fallon³, Laurie J Gordon¹, Paola Grandi², Clare I Hobbs¹, Edward Hooper-Greenhill¹, Emma J Jones¹, Robert P Law³, Armelle Le Gall¹, David Lugo¹, Anne-Marie Michon², Darren J Mitchell¹, Rab K Prinjha¹, Robert J Sheppard¹, Allan J B Watson⁴, Robert J Watson¹

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.

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.