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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Proteins
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Cell Line
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Chromones / chemistry
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Chromones / pharmacology*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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HEK293 Cells
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Humans
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Models, Molecular
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Morpholines / chemistry
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Morpholines / pharmacology*
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Piperazines / chemistry
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Piperazines / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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RNA-Binding Proteins / antagonists & inhibitors*
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RNA-Binding Proteins / metabolism
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
Substances
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BRD2 protein, human
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BRD3 protein, human
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BRD4 protein, human
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Cell Cycle Proteins
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Chromones
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Enzyme Inhibitors
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Morpholines
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Nuclear Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines
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RNA-Binding Proteins
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Transcription Factors
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LY 303511
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Protein Serine-Threonine Kinases