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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]

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