Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia

被引：84

作者：

Picaud, Sarah ^{[1
]}

Leonards, Katharina ^{[2
,3
]}

Lambert, Jean-Philippe ^{[4
]}

Dovey, Oliver ^{[5
]}

Wells, Christopher ^{[1
]}

Fedorov, Oleg ^{[1
,6
]}

Monteiro, Octovia ^{[1
,6
]}

Fujisawa, Takao ^{[7
]}

Wang, Chen-Yi ^{[7
]}

Lingard, Hannah ^{[1
]}

Tallant, Cynthia ^{[1
,6
]}

Nikbin, Nikzad ^{[8
]}

Guetzoyan, Lucie ^{[8
]}

Ingham, Richard ^{[8
]}

Ley, Steven V. ^{[8
]}

Brennan, Paul ^{[1
,6
,9
]}

Muller, Susanne ^{[1
,6
]}

Samsonova, Anastasia ^{[10
]}

Gingras, Anne-Claude ^{[4
,11
]}

Schwaller, Juerg ^{[2
,3
]}

Vassiliou, George ^{[5
,12
,13
]}

Knapp, Stefan ^{[1
,6
,14
,15
]}

Filippakopoulos, Panagis ^{[1
,7
]}

机构：

[1] Univ Oxford, Struct Genom Consortium, Old Rd Campus Res Bldg,Roosevelt Dr, Oxford OX3 7DQ, England

[2] Univ Basel, Dept Biomed, Lab Childhood Leukemia, Hebelstr 20, CH-4031 Basel, Switzerland

[3] Basel Univ Childrens Hosp, Hebelstr 20, CH-4031 Basel, Switzerland

[4] Lunenfeld Tanenbaum Res Inst, Sinai Hlth Syst, Toronto, ON, Canada

[5] Wellcome Trust Genome Campus, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[6] Univ Oxford, Target Discovery Inst, Oxford OX3 7FZ, England

[7] Univ Oxford, Ludwig Inst Canc Res, Oxford OX3 7DQ, England

[8] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England

[9] Univ Oxford, Nuffield Dept Med, Alzheimers Res UK Oxford, Res Bldg, Oxford OX3 7FZ, England

[10] Univ Oxford, CRUK MRC Oxford Inst Radiat Oncol, Dept Oncol, Oxford OX3 7DQ, England

[11] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[12] Cambridge Univ Hosp NHS Trust, Dept Haematol, Cambridge CB2 0QQ, England

[13] Univ Cambridge, Dept Haematol, Cambridge Biomed Campus, Cambridge CB2 0XY, England

[14] Goethe Univ, Inst Pharmaceut Chem, Max von Laue Str 9, D-60438 Frankfurt, Germany

[15] Goethe Univ, Buchmann Inst Life Sci, Max von Laue Str 9, D-60438 Frankfurt, Germany

来源：

SCIENCE ADVANCES | 2016年 / 2卷 / 10期

基金：

英国惠康基金; 加拿大健康研究院; 巴西圣保罗研究基金会; 加拿大创新基金会;

关键词：

GENE-EXPRESSION DATA; HISTONE RECOGNITION; STRUCTURAL BASIS; DISCOVERY; BINDING; INHIBITOR; ESTABLISHMENT; RESISTANCE; SOFTWARE; BIOLOGY;

D O I：

10.1126/sciadv.1600760

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：

Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.

引用

页数：16