[1,2,4]Triazolo[4,3-a]phthalazines: Inhibitors of Diverse Bromodomains

被引：73

作者：

Fedorov, Oleg ^{[1
,2
]}

Lingard, Hannah ^{[1
]}

Wells, Chris ^{[1
]}

Monteiro, Octovia P. ^{[1
,2
]}

Picaud, Sarah ^{[1
,3
]}

Keates, Tracy ^{[1
]}

Yapp, Clarence ^{[1
]}

Philpott, Martin ^{[1
]}

Martin, Sarah J. ^{[1
]}

Felletar, Ildiko ^{[1
]}

Marsden, Brian D. ^{[1
,4
]}

Filippakopoulos, Panagis ^{[1
,3
]}

Mueller, Susanne ^{[1
]}

Knapp, Stefan ^{[1
,2
]}

Brennan, Paul E. ^{[1
,2
]}

机构：

[1] Univ Oxford, Nuffield Dept Med, Struct Genom Consortium, Oxford OX3 7DQ, England

[2] Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Oxford OX3 7FZ, England

[3] Univ Oxford, Nuffield Dept Med, Ludwig Inst Canc Res, Oxford OX3 7DQ, England

[4] Univ Oxford, Kennedy Inst Rheumatol, Oxford OX3 7FY, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 02期

基金：

加拿大创新基金会; 英国惠康基金;

关键词：

BET BROMODOMAINS; DISCOVERY; CHROMATIN; LEUKEMIA; BINDING; BRD4; OPTIMIZATION; RECRUITMENT; DERIVATIVES; REFINEMENT;

D O I：

10.1021/jm401568s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9, CECR2, and CREBBP. This new series of compounds. is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.

引用

页码：462 / 476

页数：15

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