| Literature DB >> 32324999 |
George S Sheppard1, Le Wang1, Steven D Fidanze1, Lisa A Hasvold1, Dachun Liu1, John K Pratt1, Chang H Park1, Kenton Longenecker1, Wei Qiu1, Maricel Torrent1, Peter J Kovar1, Mai Bui1, Emily Faivre1, Xiaoli Huang1, Xiaoyu Lin1, Denise Wilcox1, Lu Zhang1, Yu Shen1, Daniel H Albert1, Terrance J Magoc1, Ganesh Rajaraman1, Warren M Kati1, Keith F McDaniel1.
Abstract
The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (∼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound 27 demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound 46 (ABBV-744).Entities:
Mesh：
Substances：
Year: 2020 PMID： 32324999 DOI： 10.1021/acs.jmedchem.0c00628
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446