The Commonly Used PI3-Kinase Probe LY294002 Is an Inhibitor of BET Bromodomains
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- 作者：Antje Dittmann ; Thilo Werner ; Chun-Wa Chung ; Mikhail M. Savitski ; Maria F?lth Savitski ; Paola Grandi ; Carsten Hopf ; Matthew Lindon ; Gitte Neubauer ; Rabinder K. Prinjha ; Marcus Bantscheff ; Gerard Drewes
- 刊名：ACS Chemical Biology
- 出版年：2014
- 出版时间：February 21, 2014
- 年：2014
- 卷：9
- 期：2
- 页码：495-502
- 全文大小：459K
- ISSN：1554-8937
文摘
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.