The Commonly Used PI3-Kinase Probe LY294002 Is an Inhibitor of BET Bromodomains
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 compri...
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| Veröffentlicht in: | ACS chemical biology 2014-02, Vol.9 (2), p.495-502 |
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| creator | Dittmann, Antje Werner, Thilo Chung, Chun-Wa Savitski, Mikhail M Fälth Savitski, Maria Grandi, Paola Hopf, Carsten Lindon, Matthew Neubauer, Gitte Prinjha, Rabinder K Bantscheff, Marcus Drewes, Gerard |
| description | 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. |
| doi_str_mv | 10.1021/cb400789e |
| format | Article |
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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.</description><identifier>ISSN: 1554-8929</identifier><identifier>EISSN: 1554-8937</identifier><identifier>DOI: 10.1021/cb400789e</identifier><identifier>PMID: 24533473</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Cell Line ; Chromones - chemistry ; Chromones - pharmacology ; Crystallography, X-Ray ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; HEK293 Cells ; Humans ; Models, Molecular ; Morpholines - chemistry ; Morpholines - pharmacology ; Nuclear Proteins - antagonists & inhibitors ; Nuclear Proteins - metabolism ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Piperazines - chemistry ; Piperazines - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - metabolism ; RNA-Binding Proteins - antagonists & inhibitors ; RNA-Binding Proteins - metabolism ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - metabolism</subject><ispartof>ACS chemical biology, 2014-02, Vol.9 (2), p.495-502</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-6a4391bc5e058f0889c22c162424e1f3695d6770ad934b33cd3af7afd7167f1b3</citedby><cites>FETCH-LOGICAL-a381t-6a4391bc5e058f0889c22c162424e1f3695d6770ad934b33cd3af7afd7167f1b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/cb400789e$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/cb400789e$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24533473$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dittmann, Antje</creatorcontrib><creatorcontrib>Werner, Thilo</creatorcontrib><creatorcontrib>Chung, Chun-Wa</creatorcontrib><creatorcontrib>Savitski, Mikhail M</creatorcontrib><creatorcontrib>Fälth Savitski, Maria</creatorcontrib><creatorcontrib>Grandi, Paola</creatorcontrib><creatorcontrib>Hopf, Carsten</creatorcontrib><creatorcontrib>Lindon, Matthew</creatorcontrib><creatorcontrib>Neubauer, Gitte</creatorcontrib><creatorcontrib>Prinjha, Rabinder K</creatorcontrib><creatorcontrib>Bantscheff, Marcus</creatorcontrib><creatorcontrib>Drewes, Gerard</creatorcontrib><title>The Commonly Used PI3-Kinase Probe LY294002 Is an Inhibitor of BET Bromodomains</title><title>ACS chemical biology</title><addtitle>ACS Chem. Biol</addtitle><description>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. 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| ispartof | ACS chemical biology, 2014-02, Vol.9 (2), p.495-502 |
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| subjects | Cell Line Chromones - chemistry Chromones - pharmacology Crystallography, X-Ray Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology HEK293 Cells Humans Models, Molecular Morpholines - chemistry Morpholines - pharmacology Nuclear Proteins - antagonists & inhibitors Nuclear Proteins - metabolism Phosphatidylinositol 3-Kinases - antagonists & inhibitors Piperazines - chemistry Piperazines - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism RNA-Binding Proteins - antagonists & inhibitors RNA-Binding Proteins - metabolism Transcription Factors - antagonists & inhibitors Transcription Factors - metabolism |
| title | The Commonly Used PI3-Kinase Probe LY294002 Is an Inhibitor of BET Bromodomains |
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