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

共 36 条

[31] The emerging mechanisms of isoform-specific PI3K signalling [J].

Vanhaesebroeck, Bart ;

Guillermet-Guibert, Julie ;

Graupera, Mariona ;

Bilanges, Benoit .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2010, 11 (05) :329-341

[32]

VLAHOS CJ, 1994, J BIOL CHEM, V269, P5241

[33]

Walker EH, 2000, MOL CELL, V6, P909, DOI 10.1016/S1097-2765(00)00088-5

[34] Drugging the PI3 Kinome: From Chemical Tools to Drugs in the Clinic [J].

Workman, Paul ;

Clarke, Paul A. ;

Raynaud, Florence I. ;

van Montfort, Rob L. M. .

CANCER RESEARCH, 2010, 70 (06) :2146-2157

[35] LY294002 inhibits TLR3/4-mediated IFN-β production via inhibition of IRF3 activation with a PI3K-independent mechanism [J].

Zhao, Wei ;

Qi, Jianni ;

Wang, Lijuan ;

Zhang, Meng ;

Wang, Peng ;

Gao, Chengjiang .

FEBS LETTERS, 2012, 586 (06) :705-710

[36] RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia [J].

Zuber, Johannes ;

Shi, Junwei ;

Wang, Eric ;

Rappaport, Amy R. ;

Herrmann, Harald ;

Sison, Edward A. ;

Magoon, Daniel ;

Qi, Jun ;

Blatt, Katharina ;

Wunderlich, Mark ;

Taylor, Meredith J. ;

Johns, Christopher ;

Chicas, Agustin ;

Mulloy, James C. ;

Kogan, Scott C. ;

Brown, Patrick ;

Valent, Peter ;

Bradner, James E. ;

Lowe, Scott W. ;

Vakoc, Christopher R. .

NATURE, 2011, 478 (7370) :524-U124

← 1 2 3 4 →