Structural Investigation of B‑Raf Paradox Breaker and Inducer Inhibitors
The V600E missense mutation in B-Raf kinase leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation of tumorigenesis. While the ATP-competitive B-Raf inhibitors block the MAPK pathway in B-Raf mutant cells, they induce conformational changes to wild-type...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-02, Vol.58 (4), p.1818-1831 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 58 |
| creator | Arora, Rohit Di Michele, Michela Stes, Elisabeth Vandermarliere, Elien Martens, Lennart Gevaert, Kris Van Heerde, Erika Linders, Joannes T. M Brehmer, Dirk Jacoby, Edgar Bonnet, Pascal |
| description | The V600E missense mutation in B-Raf kinase leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation of tumorigenesis. While the ATP-competitive B-Raf inhibitors block the MAPK pathway in B-Raf mutant cells, they induce conformational changes to wild-type B-Raf kinase domain leading to heterodimerization with C-Raf causing a paradoxical hyperactivation of MAPK pathway. A new class of inhibitors (paradox breakers) has been developed that inhibit B-RafV600E activity without agonistically affecting the MAPK pathway in wild-type B-Raf cells. In this study, we explore the structural, conformational, and cellular effects on the B-Raf kinase domain upon binding of paradox breakers and inducers. Our results indicate that a subtle structural difference between paradox inducers and breakers leads to significant conformational differences when complexed with B-Raf. This study provides a novel insight into the activation of B-Raf by ATP-competitive inhibitors and can aid in the design of more potent and selective inhibitors without agonistic function. |
| doi_str_mv | 10.1021/jm501667n |
| format | Article |
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M ; Brehmer, Dirk ; Jacoby, Edgar ; Bonnet, Pascal</creator><creatorcontrib>Arora, Rohit ; Di Michele, Michela ; Stes, Elisabeth ; Vandermarliere, Elien ; Martens, Lennart ; Gevaert, Kris ; Van Heerde, Erika ; Linders, Joannes T. M ; Brehmer, Dirk ; Jacoby, Edgar ; Bonnet, Pascal</creatorcontrib><description>The V600E missense mutation in B-Raf kinase leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation of tumorigenesis. While the ATP-competitive B-Raf inhibitors block the MAPK pathway in B-Raf mutant cells, they induce conformational changes to wild-type B-Raf kinase domain leading to heterodimerization with C-Raf causing a paradoxical hyperactivation of MAPK pathway. A new class of inhibitors (paradox breakers) has been developed that inhibit B-RafV600E activity without agonistically affecting the MAPK pathway in wild-type B-Raf cells. In this study, we explore the structural, conformational, and cellular effects on the B-Raf kinase domain upon binding of paradox breakers and inducers. Our results indicate that a subtle structural difference between paradox inducers and breakers leads to significant conformational differences when complexed with B-Raf. This study provides a novel insight into the activation of B-Raf by ATP-competitive inhibitors and can aid in the design of more potent and selective inhibitors without agonistic function.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm501667n</identifier><identifier>PMID: 25611072</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Dose-Response Relationship, Drug ; Humans ; Models, Molecular ; Molecular Structure ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins B-raf - antagonists & inhibitors ; Proto-Oncogene Proteins B-raf - genetics ; Proto-Oncogene Proteins B-raf - metabolism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2015-02, Vol.58 (4), p.1818-1831</ispartof><rights>Copyright © 2015 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a350t-b646e52d6cc35a14320de3da7a3b579645b56fab4094299e772c1baaa74f6f1c3</citedby><cites>FETCH-LOGICAL-a350t-b646e52d6cc35a14320de3da7a3b579645b56fab4094299e772c1baaa74f6f1c3</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/jm501667n$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm501667n$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2769,27085,27933,27934,56747,56797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25611072$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Arora, Rohit</creatorcontrib><creatorcontrib>Di Michele, Michela</creatorcontrib><creatorcontrib>Stes, Elisabeth</creatorcontrib><creatorcontrib>Vandermarliere, Elien</creatorcontrib><creatorcontrib>Martens, Lennart</creatorcontrib><creatorcontrib>Gevaert, Kris</creatorcontrib><creatorcontrib>Van Heerde, Erika</creatorcontrib><creatorcontrib>Linders, Joannes T. M</creatorcontrib><creatorcontrib>Brehmer, Dirk</creatorcontrib><creatorcontrib>Jacoby, Edgar</creatorcontrib><creatorcontrib>Bonnet, Pascal</creatorcontrib><title>Structural Investigation of B‑Raf Paradox Breaker and Inducer Inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The V600E missense mutation in B-Raf kinase leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation of tumorigenesis. While the ATP-competitive B-Raf inhibitors block the MAPK pathway in B-Raf mutant cells, they induce conformational changes to wild-type B-Raf kinase domain leading to heterodimerization with C-Raf causing a paradoxical hyperactivation of MAPK pathway. A new class of inhibitors (paradox breakers) has been developed that inhibit B-RafV600E activity without agonistically affecting the MAPK pathway in wild-type B-Raf cells. In this study, we explore the structural, conformational, and cellular effects on the B-Raf kinase domain upon binding of paradox breakers and inducers. Our results indicate that a subtle structural difference between paradox inducers and breakers leads to significant conformational differences when complexed with B-Raf. This study provides a novel insight into the activation of B-Raf by ATP-competitive inhibitors and can aid in the design of more potent and selective inhibitors without agonistic function.</description><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins B-raf - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Proto-Oncogene Proteins B-raf - metabolism</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>eNptkEtOwzAQQC0EoqWw4AIoGyRYBPx3s6QVn6BKID7raOI4kJLExU4Q7LgCV-QkGLV0xWpm8fQ08xDaJ_iEYEpO543ARErVbqAhERTHfIz5JhpiTGlMJWUDtOP9HGPMCGXbaECFJAQrOkTX953rddc7qKO0fTO-q56gq2wb2TKafH9-3UEZ3YKDwr5HE2fgxbgI2iLARa_DnrbPVV511vldtFVC7c3eao7Q48X5w_Qqnt1cptOzWQxM4C7OJZdG0EJqzQQQziguDCtAAcuFSiQXuZAl5BwnnCaJUYpqkgOA4qUsiWYjdLT0Lpx97cPFWVN5beoaWmN7nxEpEhVqkHFAj5eodtZ7Z8ps4aoG3EdGcPabLlunC-zBStvnjSnW5F-rABwuAdA-m9veteHLf0Q_Nx91cQ</recordid><startdate>20150226</startdate><enddate>20150226</enddate><creator>Arora, Rohit</creator><creator>Di Michele, Michela</creator><creator>Stes, Elisabeth</creator><creator>Vandermarliere, Elien</creator><creator>Martens, Lennart</creator><creator>Gevaert, Kris</creator><creator>Van Heerde, Erika</creator><creator>Linders, Joannes T. 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| subjects | Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Dose-Response Relationship, Drug Humans Models, Molecular Molecular Structure Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism Structure-Activity Relationship |
| title | Structural Investigation of B‑Raf Paradox Breaker and Inducer Inhibitors |
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