Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe

Bradley, Erin and Fusani, Lucia and Chung, Chun-wa and Craggs, Peter D. and Demont, Emmanuel H. and Humphreys, Philip G. and Mitchell, Darren J. and Phillipou, Alexander and Rioja, Inmaculada and Shah, Rishi R. and Wellaway, Christopher R. and Prinjha, Rab K. and Palmer, David S. and Kerr, William J. and Reid, Marc and Wall, Ian D. and Cookson, Rosa (2023) Structure-guided design of a domain-selective bromodomain and extra terminal N-terminal bromodomain chemical probe. Journal of Medicinal Chemistry, 66 (23). pp. 15728-15749. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.3c00906)

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Abstract

Small molecule mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain dataset through a lipophilic efficiency lens, which enabled identification of a BD1 domain biased benzimidazole series. Structure guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300–1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

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