Discovery and lead identification of quinazoline-based BRD4 inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Yang, Shyh-Ming¹  Urban, Daniel J.¹  Yoshioka, Makoto²  Strovel, Jeffrey W.²  Fletcher, Steven³  Wang, Amy Q.¹  Xu, Xin¹  Shah, Pranav¹  Hu, Xin¹  Hall, Matthew D.¹  Jadhav, Ajit¹  Maloney, David J.¹ 

[1] NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA

[2] ConverGene LLC, 3093 Beverly Lane,Unit C, Cambridge, MD 21613 USA

[3] Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, 20 North Pine St, Baltimore, MD 21201 USA

关键词: BET inhibitor;    BRD4;    Bromodomain;    Quinazoline;    Cancer;    Inflammation;   

DOI  :  10.1016/j.bmcl.2018.08.039

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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