Selective inhibition of BET bromodomains

被引：3249

作者：

Filippakopoulos, Panagis ^{[1
]}

Qi, Jun ^{[2
]}

Picaud, Sarah ^{[1
]}

Shen, Yao ^{[3
,4
]}

Smith, William B. ^{[2
]}

Fedorov, Oleg ^{[1
]}

Morse, Elizabeth M. ^{[2
]}

Keates, Tracey ^{[1
]}

Hickman, Tyler T. ^{[5
]}

Felletar, Ildiko ^{[1
]}

Philpott, Martin ^{[1
]}

Munro, Shonagh ^{[6
]}

McKeown, Michael R. ^{[2
,7
]}

Wang, Yuchuan ^{[8
]}

Christie, Amanda L. ^{[9
]}

West, Nathan ^{[2
]}

Cameron, Michael J. ^{[5
]}

Schwartz, Brian ^{[5
]}

Heightman, Tom D. ^{[1
]}

La Thangue, Nicholas ^{[6
]}

French, Christopher A. ^{[5
]}

Wiest, Olaf ^{[3
,4
]}

Kung, Andrew L. ^{[9
,10
,11
]}

Knapp, Stefan ^{[1
,6
]}

Bradner, James E. ^{[2
,7
]}

机构：

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

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA

[4] Univ Notre Dame, Walther Canc Res Ctr, Notre Dame, IN 46556 USA

[5] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA

[6] Univ Oxford, Dept Clin Pharmacol, Oxford OX3 7DQ, England

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA

[10] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[11] Childrens Hosp, Boston, MA 02115 USA

来源：

NATURE | 2010年 / 468卷 / 7327期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

ABL TYROSINE KINASE; PROTEIN BRD4; P-TEFB; AGGRESSIVE CARCINOMA; MITOTIC CHROMOSOMES; SIGNAL-TRANSDUCTION; STRUCTURAL BASIS; CHEMICAL PROBES; IN-VIVO; LEUKEMIA;

D O I：

10.1038/nature09504

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

引用

页码：1067 / 1073

页数：7

共 43 条

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