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. 2016 May 9;7(6):552-7.
doi: 10.1021/acsmedchemlett.6b00092. eCollection 2016 Jun 9.

GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain

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

GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain

Paul Bamborough et al. ACS Med Chem Lett. .

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
X-ray structure of BRPF1 with 1 (PDB 4UYE).
Figure 2
Figure 2
(A) GRID map analysis using the BRPF1 structure of compound 1 (PDB 4UYE). Methyl probe is shown in orange mesh. (B). X-ray structure of BRPF1 (cyan, PDB 5G4R) with 34, overlaid with BRPF2 apo (magenta, PDB 3RCW).
Figure 3
Figure 3
X-ray structures of BRPF1 with 34 (cyan, PDB 5G4R) and 38 (magenta, PDB 5G4S).
Figure 4
Figure 4
Potency for endogenous cellular BRPF1. pIC50 of 34 for BRPF1 and BRD3 measured in a chemoproteomic competition binding assay (Supplementary Methods, Supporting Information).
See this image and copyright information in PMC

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