The Commonly Used PI3-Kinase Probe LY294002 Is an Inhibitor of BET Bromodomains

被引：93

作者：

Dittmann, Antje ^{[1
]}

Werner, Thilo ^{[1
]}

Chung, Chun-Wa ^{[2
]}

Savitski, Mikhail M. ^{[1
]}

Savitski, Maria Faelth ^{[1
]}

Grandi, Paola ^{[1
]}

Hopf, Carsten ^{[1
]}

Lindon, Matthew ^{[3
]}

Neubauer, Gitte ^{[1
]}

Prinjha, Rabinder K. ^{[3
]}

Bantscheff, Marcus ^{[1
]}

Drewes, Gerard ^{[1
]}

机构：

[1] Cellzome GmbH, D-69117 Heidelberg, Germany

[2] GlaxoSmithKline Med Res Ctr, Stevenage SG1 2NY, Herts, England

[3] GlaxoSmithKline Med Res Ctr, Epinova DPU, Stevenage SG1 2NY, Herts, England

来源：

ACS CHEMICAL BIOLOGY | 2014年 / 9卷 / 02期

关键词：

SELECTIVE-INHIBITION; KINASE; TARGET; ACTIVATION; PROTEIN; BRD4; CHEMOPROTEOMICS; MECHANISMS; DISCOVERY; 3-KINASE;

D O I：

10.1021/cb400789e

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A commonly used small-molecule probe in cell-signaling research is the phosphoinositide 3-kinase inhibitor LY294002. Quantitative chemoproteomic profiling shows that LY294002 and LY303511, a close analogue devoid of PI3K activity, inhibit the BET bromodomain proteins BRD2, BRD3, and BRD4 that comprise a family of targets structurally unrelated to PI3K. Both compounds competitively inhibit acetyl-lysine binding of the first but not the second bromodomain of BET proteins in cell extracts. X-ray crystallography shows that the chromen-4-one scaffold represents a new bromodomain pharmacophore and establishes LY294002 as a dual kinase and BET-bromodomain inhibitor, whereas LY303511 exhibits anti-inflammatory and antiproliferative effects similar to the recently discovered BET inhibitors.

引用

页码：495 / 502

页数：8

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