1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain

Emmanuel H Demont; Paul Bamborough; Chun-Wa Chung; Peter D Craggs; David Fallon; Laurie J Gordon; Paola Grandi; Clare I Hobbs; Jameed Hussain; Emma J Jones; Armelle Le Gall; Anne-Marie Michon; Darren J Mitchell; Rab K Prinjha; Andy D Roberts; Robert J Sheppard; Robert J Watson

doi:10.1021/ml5002932

1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain

ACS Med Chem Lett. 2014 Sep 10;5(11):1190-5. doi: 10.1021/ml5002932. eCollection 2014 Nov 13.

Authors

Emmanuel H Demont¹, Paul Bamborough¹, Chun-Wa Chung¹, Peter D Craggs¹, David Fallon¹, Laurie J Gordon¹, Paola Grandi², Clare I Hobbs¹, Jameed Hussain¹, Emma J Jones¹, Armelle Le Gall¹, Anne-Marie Michon², Darren J Mitchell¹, Rab K Prinjha¹, Andy D Roberts³, Robert J Sheppard¹, Robert J Watson¹

Affiliations

¹ Epinova Discovery Performance Unit and Molecular Discovery Research, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
² Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
³ DMPK, GlaxoSmithKline , Park Road, Ware SG12 0DP, U.K.

Abstract

The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure-activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomain.

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