A Novel, Selective, and Efficacious Nanomolar Pyridopyrazinone Inhibitor of V600EBRAF
Oncogenic BRAF is a critical driver of proliferation and survival and is thus a validated therapeutic target in cancer. We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, (V600E)BRAF. 1t inhibits signaling downstream of (V600E)BRAF in cancer cells, blocking DN...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2010-10, Vol.70 (20), p.8036-8044 |
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| creator | WHITTAKER, Steven MENARD, Delphine LAMBROS, Maryou REIS-FILHO, Jorge S MARAIS, Richard SPRINGER, Caroline J KIRK, Ruth OGILVIE, Lesley HEDLEY, Douglas ZAMBON, Alfonso LOPES, Filipa PREECE, Natasha MANNE, Helen RANA, Sareena |
| description | Oncogenic BRAF is a critical driver of proliferation and survival and is thus a validated therapeutic target in cancer. We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, (V600E)BRAF. 1t inhibits signaling downstream of (V600E)BRAF in cancer cells, blocking DNA synthesis, and inhibiting proliferation. Importantly, we show that 1t is considerably more selective for mutated BRAF cancer cell lines compared with wild-type BRAF lines. The inhibitor is well tolerated in mice and exhibits excellent oral bioavailability (F = 71%). Suppression of (V600E)BRAF-mediated signaling in human tumor xenografts was observed following oral administration of a single dose of 1t. As expected, the growth rate in vivo of a wild-type BRAF human tumor xenograft model is unaffected by inhibitor 1t. In contrast, 1t elicits significant therapeutic responses in mutant BRAF-driven human melanoma xenografts. |
| doi_str_mv | 10.1158/0008-5472.can-10-1366 |
| format | Article |
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We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, (V600E)BRAF. 1t inhibits signaling downstream of (V600E)BRAF in cancer cells, blocking DNA synthesis, and inhibiting proliferation. Importantly, we show that 1t is considerably more selective for mutated BRAF cancer cell lines compared with wild-type BRAF lines. The inhibitor is well tolerated in mice and exhibits excellent oral bioavailability (F = 71%). Suppression of (V600E)BRAF-mediated signaling in human tumor xenografts was observed following oral administration of a single dose of 1t. As expected, the growth rate in vivo of a wild-type BRAF human tumor xenograft model is unaffected by inhibitor 1t. In contrast, 1t elicits significant therapeutic responses in mutant BRAF-driven human melanoma xenografts.</description><identifier>ISSN: 0008-5472</identifier><identifier>ISSN: 1538-7445</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-10-1366</identifier><identifier>PMID: 20807807</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Administration, Oral ; Amino Acid Substitution ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Cell Division ; Cell Line, Tumor ; Cell Survival ; Colonic Neoplasms - genetics ; Colonic Neoplasms - pathology ; Enzyme Inhibitors - pharmacology ; Enzyme-Linked Immunosorbent Assay ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Female ; Humans ; Medical sciences ; Melanoma - genetics ; Melanoma - pathology ; Mice ; Mice, Inbred BALB C ; Models, Molecular ; Neoplasm Proteins - genetics ; Nucleic Acid Hybridization ; Pharmacology. Drug treatments ; Phosphorylation ; Proto-Oncogene Proteins B-raf - genetics ; Transplantation, Heterologous ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2010-10, Vol.70 (20), p.8036-8044</ispartof><rights>2015 INIST-CNRS</rights><rights>2010 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3516-633581bf130e163717d52ce13556248e526032793efc3e805f23720fe395067d3</citedby><cites>FETCH-LOGICAL-c3516-633581bf130e163717d52ce13556248e526032793efc3e805f23720fe395067d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23324880$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20807807$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>WHITTAKER, Steven</creatorcontrib><creatorcontrib>MENARD, Delphine</creatorcontrib><creatorcontrib>LAMBROS, Maryou</creatorcontrib><creatorcontrib>REIS-FILHO, Jorge S</creatorcontrib><creatorcontrib>MARAIS, Richard</creatorcontrib><creatorcontrib>SPRINGER, Caroline J</creatorcontrib><creatorcontrib>KIRK, Ruth</creatorcontrib><creatorcontrib>OGILVIE, Lesley</creatorcontrib><creatorcontrib>HEDLEY, Douglas</creatorcontrib><creatorcontrib>ZAMBON, Alfonso</creatorcontrib><creatorcontrib>LOPES, Filipa</creatorcontrib><creatorcontrib>PREECE, Natasha</creatorcontrib><creatorcontrib>MANNE, Helen</creatorcontrib><creatorcontrib>RANA, Sareena</creatorcontrib><title>A Novel, Selective, and Efficacious Nanomolar Pyridopyrazinone Inhibitor of V600EBRAF</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Oncogenic BRAF is a critical driver of proliferation and survival and is thus a validated therapeutic target in cancer. We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, (V600E)BRAF. 1t inhibits signaling downstream of (V600E)BRAF in cancer cells, blocking DNA synthesis, and inhibiting proliferation. Importantly, we show that 1t is considerably more selective for mutated BRAF cancer cell lines compared with wild-type BRAF lines. The inhibitor is well tolerated in mice and exhibits excellent oral bioavailability (F = 71%). Suppression of (V600E)BRAF-mediated signaling in human tumor xenografts was observed following oral administration of a single dose of 1t. As expected, the growth rate in vivo of a wild-type BRAF human tumor xenograft model is unaffected by inhibitor 1t. In contrast, 1t elicits significant therapeutic responses in mutant BRAF-driven human melanoma xenografts.</description><subject>Administration, Oral</subject><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Division</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colonic Neoplasms - pathology</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Melanoma - genetics</subject><subject>Melanoma - pathology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Models, Molecular</subject><subject>Neoplasm Proteins - genetics</subject><subject>Nucleic Acid Hybridization</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorylation</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Transplantation, Heterologous</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkdtuEzEQhi0EoqHwCKC9Qdx02_FOfMgNUojSg1QFBJRby_GOqdHGTu0kUnj6bto0UGkka8bf_GP_w9h7DqecC30GALoWQ9WcOhtrDjVHKV-wAReoazUcipdscGCO2JtS_vSp4CBes6MGNKg-BuxmXM3ShrqT6gd15FZhQyeVjW019T4460Jal2pmY1qkzubq2zaHNi232f4NMUWqruJtmIdVylXy1S8JMP3yfXz-lr3ytiv0bn8es5vz6c_JZX399eJqMr6uHQoua4koNJ97jkBcouKqFY0jjkLIZqhJNBKwUSMk75A0CN-gasATjgRI1eIx-_you1zPF9Q6iqtsO7PMYWHz1iQbzPObGG7N77QxCMD5iPcCn_YCOd2tqazMIhRHXWcj9T83SmiNSknZk-KRdDmVkskfpnAwu42Yndtm57aZjGcPVXzo-_D_Ew9dTyvogY97wBZnO59tdKH84xB7KzTgPYZKkl4</recordid><startdate>20101015</startdate><enddate>20101015</enddate><creator>WHITTAKER, Steven</creator><creator>MENARD, Delphine</creator><creator>LAMBROS, Maryou</creator><creator>REIS-FILHO, Jorge S</creator><creator>MARAIS, Richard</creator><creator>SPRINGER, Caroline J</creator><creator>KIRK, Ruth</creator><creator>OGILVIE, Lesley</creator><creator>HEDLEY, Douglas</creator><creator>ZAMBON, Alfonso</creator><creator>LOPES, Filipa</creator><creator>PREECE, Natasha</creator><creator>MANNE, Helen</creator><creator>RANA, Sareena</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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><scope>5PM</scope></search><sort><creationdate>20101015</creationdate><title>A Novel, Selective, and Efficacious Nanomolar Pyridopyrazinone Inhibitor of V600EBRAF</title><author>WHITTAKER, Steven ; MENARD, Delphine ; LAMBROS, Maryou ; REIS-FILHO, Jorge S ; MARAIS, Richard ; SPRINGER, Caroline J ; KIRK, Ruth ; OGILVIE, Lesley ; HEDLEY, Douglas ; ZAMBON, Alfonso ; LOPES, Filipa ; PREECE, Natasha ; MANNE, Helen ; RANA, Sareena</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3516-633581bf130e163717d52ce13556248e526032793efc3e805f23720fe395067d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Administration, Oral</topic><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Division</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival</topic><topic>Colonic Neoplasms - genetics</topic><topic>Colonic Neoplasms - pathology</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Melanoma - genetics</topic><topic>Melanoma - pathology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Models, Molecular</topic><topic>Neoplasm Proteins - genetics</topic><topic>Nucleic Acid Hybridization</topic><topic>Pharmacology. 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We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, (V600E)BRAF. 1t inhibits signaling downstream of (V600E)BRAF in cancer cells, blocking DNA synthesis, and inhibiting proliferation. Importantly, we show that 1t is considerably more selective for mutated BRAF cancer cell lines compared with wild-type BRAF lines. The inhibitor is well tolerated in mice and exhibits excellent oral bioavailability (F = 71%). Suppression of (V600E)BRAF-mediated signaling in human tumor xenografts was observed following oral administration of a single dose of 1t. As expected, the growth rate in vivo of a wild-type BRAF human tumor xenograft model is unaffected by inhibitor 1t. In contrast, 1t elicits significant therapeutic responses in mutant BRAF-driven human melanoma xenografts.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>20807807</pmid><doi>10.1158/0008-5472.can-10-1366</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0008-5472 |
| ispartof | Cancer research (Chicago, Ill.), 2010-10, Vol.70 (20), p.8036-8044 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Administration, Oral Amino Acid Substitution Animals Antineoplastic agents Biological and medical sciences Breast Neoplasms - genetics Breast Neoplasms - pathology Cell Division Cell Line, Tumor Cell Survival Colonic Neoplasms - genetics Colonic Neoplasms - pathology Enzyme Inhibitors - pharmacology Enzyme-Linked Immunosorbent Assay Extracellular Signal-Regulated MAP Kinases - metabolism Female Humans Medical sciences Melanoma - genetics Melanoma - pathology Mice Mice, Inbred BALB C Models, Molecular Neoplasm Proteins - genetics Nucleic Acid Hybridization Pharmacology. Drug treatments Phosphorylation Proto-Oncogene Proteins B-raf - genetics Transplantation, Heterologous Tumors |
| title | A Novel, Selective, and Efficacious Nanomolar Pyridopyrazinone Inhibitor of V600EBRAF |
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