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Discovery and lead identification of quinazoline-based BRD4 inhibitors |
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| Authors: | Shyh-Ming Yang Daniel J Urban Makoto Yoshioka Jeffrey W Strovel Steven Fletcher Amy Q Wang Xin Xu Pranav Shah Xin Hu Matthew D Hall Ajit Jadhav David J Maloney |
| Institution: | 1. National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States;2. ConverGene LLC., 3093 Beverly Lane, Unit C, Cambridge, MD 21613, United States;3. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, MD 21201, United States |
| Abstract: | A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization. |
| Keywords: | BET inhibitor BRD4 Bromodomain Quinazoline Cancer Inflammation |
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