JOURNAL ARTICLE

The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains

Antje Dittmann, Thilo Werner, Chun-Wa Chung, Mikhail M Savitski, Maria Fälth Savitski, Paola Grandi, Carsten Hopf, Matthew Lindon, Gitte Neubauer, Rabinder K Prinjha, Marcus Bantscheff, Gerard Drewes
ACS Chemical Biology 2014 February 21, 9 (2): 495-502
24533473
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.

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