Structural Basis for Isoform Selectivity in a Class of Benzothiazole Inhibitors of Phosphoinositide 3‑Kinase γ
Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered tha...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-01, Vol.58 (1), p.517-521 |
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| container_title | Journal of medicinal chemistry |
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| creator | Collier, Philip N. Martinez-Botella, Gabriel Cornebise, Mark Cottrell, Kevin M. Doran, John D. Griffith, James P. Mahajan, Sudipta Maltais, François Moody, Cameron S. Huck, Emilie Porter Wang, Tiansheng Aronov, Alex M. |
| description | Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region. |
| doi_str_mv | 10.1021/jm500362j |
| format | Article |
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Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. 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Med. Chem</addtitle><description>Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.</description><subject>Benzothiazoles - chemistry</subject><subject>Benzothiazoles - metabolism</subject><subject>Benzothiazoles - pharmacology</subject><subject>Class Ib Phosphatidylinositol 3-Kinase - antagonists & inhibitors</subject><subject>Class Ib Phosphatidylinositol 3-Kinase - chemistry</subject><subject>Class Ib Phosphatidylinositol 3-Kinase - metabolism</subject><subject>Crystallography, X-Ray</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - chemistry</subject><subject>Isoenzymes - metabolism</subject><subject>Molecular Structure</subject><subject>Protein Binding</subject><subject>Protein Structure, Tertiary</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0EtKxEAUBdBCFG0_AzcgNRF0EK1ffkO78dMoKKjjUJW80NUkqbZeRdCRW3At7sNFuBKjrY4c3cE7XHiXkF3OjjgT_HjexozJRMxXyIjHgkUqY2qVjBgTIhKJkBtkE3HOBsSFXCcbQqWxSlg-Ig-3wfdl6L1u6FijRVo7T6fohmjpLTRQBvtowxO1HdV00mhE6mo6hu7ZhZnVz64BOu1m1tjg_PftZuZwMXO2c2iDrYDKj5fXS9tpBPr-tk3Wat0g7PzkFrk_O72bXERX1-fTyclVpCWPQyTqsuJxWUMFkGppZB5XmWZK1ylkpuIAUgmdqDxNUlObXAhmssxkCTOqzEwut8jBsnfh3UMPGIrWYglNoztwPRY8UXGaKp7KgR4uaekdooe6WHjbav9UcFZ8LVz8LTzYvZ_a3rRQ_cnfSQewvwS6xGLuet8NX_5T9An_FoWV</recordid><startdate>20150108</startdate><enddate>20150108</enddate><creator>Collier, Philip N.</creator><creator>Martinez-Botella, Gabriel</creator><creator>Cornebise, Mark</creator><creator>Cottrell, Kevin M.</creator><creator>Doran, John D.</creator><creator>Griffith, James P.</creator><creator>Mahajan, Sudipta</creator><creator>Maltais, François</creator><creator>Moody, Cameron S.</creator><creator>Huck, Emilie Porter</creator><creator>Wang, Tiansheng</creator><creator>Aronov, Alex M.</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150108</creationdate><title>Structural Basis for Isoform Selectivity in a Class of Benzothiazole Inhibitors of Phosphoinositide 3‑Kinase γ</title><author>Collier, Philip N. ; Martinez-Botella, Gabriel ; Cornebise, Mark ; Cottrell, Kevin M. ; Doran, John D. ; Griffith, James P. ; Mahajan, Sudipta ; Maltais, François ; Moody, Cameron S. ; Huck, Emilie Porter ; Wang, Tiansheng ; Aronov, Alex M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-2fcd15cfedee7a3b395d8a04af7e8bd1ee342a649767bfb9220b88b860b4c8b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Benzothiazoles - chemistry</topic><topic>Benzothiazoles - metabolism</topic><topic>Benzothiazoles - pharmacology</topic><topic>Class Ib Phosphatidylinositol 3-Kinase - antagonists & inhibitors</topic><topic>Class Ib Phosphatidylinositol 3-Kinase - chemistry</topic><topic>Class Ib Phosphatidylinositol 3-Kinase - metabolism</topic><topic>Crystallography, X-Ray</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - chemistry</topic><topic>Isoenzymes - metabolism</topic><topic>Molecular Structure</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Collier, Philip N.</creatorcontrib><creatorcontrib>Martinez-Botella, Gabriel</creatorcontrib><creatorcontrib>Cornebise, Mark</creatorcontrib><creatorcontrib>Cottrell, Kevin M.</creatorcontrib><creatorcontrib>Doran, John D.</creatorcontrib><creatorcontrib>Griffith, James P.</creatorcontrib><creatorcontrib>Mahajan, Sudipta</creatorcontrib><creatorcontrib>Maltais, François</creatorcontrib><creatorcontrib>Moody, Cameron S.</creatorcontrib><creatorcontrib>Huck, Emilie Porter</creatorcontrib><creatorcontrib>Wang, Tiansheng</creatorcontrib><creatorcontrib>Aronov, Alex M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Collier, Philip N.</au><au>Martinez-Botella, Gabriel</au><au>Cornebise, Mark</au><au>Cottrell, Kevin M.</au><au>Doran, John D.</au><au>Griffith, James P.</au><au>Mahajan, Sudipta</au><au>Maltais, François</au><au>Moody, Cameron S.</au><au>Huck, Emilie Porter</au><au>Wang, Tiansheng</au><au>Aronov, Alex M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural Basis for Isoform Selectivity in a Class of Benzothiazole Inhibitors of Phosphoinositide 3‑Kinase γ</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| subjects | Benzothiazoles - chemistry Benzothiazoles - metabolism Benzothiazoles - pharmacology Class Ib Phosphatidylinositol 3-Kinase - antagonists & inhibitors Class Ib Phosphatidylinositol 3-Kinase - chemistry Class Ib Phosphatidylinositol 3-Kinase - metabolism Crystallography, X-Ray Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Humans Hydrophobic and Hydrophilic Interactions Isoenzymes - antagonists & inhibitors Isoenzymes - chemistry Isoenzymes - metabolism Molecular Structure Protein Binding Protein Structure, Tertiary Structure-Activity Relationship |
| title | Structural Basis for Isoform Selectivity in a Class of Benzothiazole Inhibitors of Phosphoinositide 3‑Kinase γ |
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