title: The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains.
abstract: 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.
authors.affiliation: Cellzome GmbH , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Dittmann
authors.forename: Thilo
authors.initials: T
authors.lastname: Werner
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Savitski
authors.forename: Maria
authors.initials: M
authors.lastname: Fälth Savitski
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
authors.forename: Matthew
authors.initials: M
authors.lastname: Lindon
authors.forename: Gitte
authors.initials: G
authors.lastname: Neubauer
authors.forename: Rabinder K
authors.initials: RK
authors.lastname: Prinjha
authors.forename: Marcus
authors.initials: M
authors.lastname: Bantscheff
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
mesh_terms: D018797:Cell Cycle Proteins; D002460:Cell Line; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C093555:LY 303511; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one