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Discovery and lead identification of quinazoline-based BRD4 inhibitors.

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.

SUBMITTER: Yang SM

PROVIDER: S-EPMC7392372 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Discovery and lead identification of quinazoline-based BRD4 inhibitors.

Yang Shyh-Ming SM Urban Daniel J DJ Yoshioka Makoto M Strovel Jeffrey W JW Fletcher Steven S Wang Amy Q AQ Xu Xin X Shah Pranav P Hu Xin X Hall Matthew D MD Jadhav Ajit A Maloney David J DJ

Bioorganic & medicinal chemistry letters 20180831 21

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 wh ...[more]

PMID: 30268702

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