Structure-based design of a bromodomain and extraterminal domain (BET) inhibitor selective for the N-terminal bromodomains that retains an anti-inflammatory and antiproliferative phenotype

Wellaway, Christopher R. and Bamborough, Paul and Bernard, Sharon G. and Chung, Chun-wa and Craggs, Peter D. and Cutler, Leanne and Demont, Emmanuel H. and Evans, John P. and Gordon, Laurie and Karamshi, Bhumika and Lewis, Antonia J. and Lindon, Matthew J. and Mitchell, Darren J. and Rioja, Inmaculada and Soden, Peter E. and Taylor, Simon and Watson, Robert J. and Willis, Rob and Woolven, James M. and Wyspiańska, Beata S. and Kerr, William J. and Prinjha, Rab K. (2020) Structure-based design of a bromodomain and extraterminal domain (BET) inhibitor selective for the N-terminal bromodomains that retains an anti-inflammatory and antiproliferative phenotype. Journal of Medicinal Chemistry. ISSN 0022-2623

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    Abstract

    The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects.