VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia
In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-01, Vol.55 (2), p.725-734 |
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| container_title | Journal of medicinal chemistry |
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| creator | Heidary, David K Huang, George Boucher, Diane Ma, Jianguo Forster, Cornelia Grey, Ron Xu, Jinwang Arnost, Michael Choquette, Deborah Chen, Guanjing Zhou, Jie-Hua Yao, Yung-Mae Ball, Edward D Namchuk, Mark Davies, Robert J Henkel, Greg |
| description | In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K i values of |
| doi_str_mv | 10.1021/jm201198w |
| format | Article |
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To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K i values of <1 nM and a cellular IC50 between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm201198w</identifier><identifier>PMID: 22221201</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Cell Survival - drug effects ; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors ; Humans ; Leukemia, Myeloid, Acute - drug therapy ; Male ; Mice ; Mice, Inbred BALB C ; Morpholines - pharmacology ; Neoplasm Transplantation ; Proto-Oncogene Proteins c-kit - antagonists & inhibitors ; Serum ; Triazoles - pharmacology ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 2012-01, Vol.55 (2), p.725-734</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a314t-4399ca067151fb0f1a716265eca834a19ab918ea9dc355773f3f57d4990280ba3</citedby><cites>FETCH-LOGICAL-a314t-4399ca067151fb0f1a716265eca834a19ab918ea9dc355773f3f57d4990280ba3</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/jm201198w$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm201198w$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22221201$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Heidary, David K</creatorcontrib><creatorcontrib>Huang, George</creatorcontrib><creatorcontrib>Boucher, Diane</creatorcontrib><creatorcontrib>Ma, Jianguo</creatorcontrib><creatorcontrib>Forster, Cornelia</creatorcontrib><creatorcontrib>Grey, Ron</creatorcontrib><creatorcontrib>Xu, Jinwang</creatorcontrib><creatorcontrib>Arnost, Michael</creatorcontrib><creatorcontrib>Choquette, Deborah</creatorcontrib><creatorcontrib>Chen, Guanjing</creatorcontrib><creatorcontrib>Zhou, Jie-Hua</creatorcontrib><creatorcontrib>Yao, Yung-Mae</creatorcontrib><creatorcontrib>Ball, Edward D</creatorcontrib><creatorcontrib>Namchuk, Mark</creatorcontrib><creatorcontrib>Davies, Robert J</creatorcontrib><creatorcontrib>Henkel, Greg</creatorcontrib><title>VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K i values of <1 nM and a cellular IC50 between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>fms-Like Tyrosine Kinase 3 - antagonists & inhibitors</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Morpholines - pharmacology</subject><subject>Neoplasm Transplantation</subject><subject>Proto-Oncogene Proteins c-kit - antagonists & inhibitors</subject><subject>Serum</subject><subject>Triazoles - pharmacology</subject><subject>Tumor Cells, Cultured</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1LAzEQhoMotlYP_gHJRcTDaibZT2-lfhWrglTxtmTTiW7d3dRkV-m_N6XakwPDHOZ5X2ZeQg6BnQHjcD6vOQPI0u8t0oeIsyBMWbhN-oxxHvCYix7Zc27OGBPAxS7pcV_gNX3y9vIaCM4v6JA-mC-s6GUnK_qEChetsXS6tMaVDdK7spEO6bh5L4tytdG-23ekU4uyrbFpqdF0qLoW6f0SK_OGjekcnWD3gXUp98mOlpXDg985IM_XV9PRbTB5vBmPhpNACgjbIBRZpiSLE4hAF0yDTCDmcYRKpiKUkMkigxRlNlMiipJEaKGjZBZmGeMpK6QYkJO178Kazw5dm9elU1hVskF_T-7VKxnEnjxdk8q_6CzqfGHLWtplDixfxZpvYvXs0a9rV9Q425B_OXrgeA1I5fK56Wzjn_zH6AcvaHzX</recordid><startdate>20120126</startdate><enddate>20120126</enddate><creator>Heidary, David K</creator><creator>Huang, George</creator><creator>Boucher, Diane</creator><creator>Ma, Jianguo</creator><creator>Forster, Cornelia</creator><creator>Grey, Ron</creator><creator>Xu, Jinwang</creator><creator>Arnost, Michael</creator><creator>Choquette, Deborah</creator><creator>Chen, Guanjing</creator><creator>Zhou, Jie-Hua</creator><creator>Yao, Yung-Mae</creator><creator>Ball, Edward D</creator><creator>Namchuk, Mark</creator><creator>Davies, Robert J</creator><creator>Henkel, Greg</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>20120126</creationdate><title>VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia</title><author>Heidary, David K ; Huang, George ; Boucher, Diane ; Ma, Jianguo ; Forster, Cornelia ; Grey, Ron ; Xu, Jinwang ; Arnost, Michael ; Choquette, Deborah ; Chen, Guanjing ; Zhou, Jie-Hua ; Yao, Yung-Mae ; Ball, Edward D ; Namchuk, Mark ; Davies, Robert J ; Henkel, Greg</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a314t-4399ca067151fb0f1a716265eca834a19ab918ea9dc355773f3f57d4990280ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>fms-Like Tyrosine Kinase 3 - antagonists & inhibitors</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Morpholines - pharmacology</topic><topic>Neoplasm Transplantation</topic><topic>Proto-Oncogene Proteins c-kit - antagonists & inhibitors</topic><topic>Serum</topic><topic>Triazoles - pharmacology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Heidary, David K</creatorcontrib><creatorcontrib>Huang, George</creatorcontrib><creatorcontrib>Boucher, Diane</creatorcontrib><creatorcontrib>Ma, Jianguo</creatorcontrib><creatorcontrib>Forster, Cornelia</creatorcontrib><creatorcontrib>Grey, Ron</creatorcontrib><creatorcontrib>Xu, Jinwang</creatorcontrib><creatorcontrib>Arnost, Michael</creatorcontrib><creatorcontrib>Choquette, Deborah</creatorcontrib><creatorcontrib>Chen, Guanjing</creatorcontrib><creatorcontrib>Zhou, Jie-Hua</creatorcontrib><creatorcontrib>Yao, Yung-Mae</creatorcontrib><creatorcontrib>Ball, Edward D</creatorcontrib><creatorcontrib>Namchuk, Mark</creatorcontrib><creatorcontrib>Davies, Robert J</creatorcontrib><creatorcontrib>Henkel, Greg</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>Heidary, David K</au><au>Huang, George</au><au>Boucher, Diane</au><au>Ma, Jianguo</au><au>Forster, Cornelia</au><au>Grey, Ron</au><au>Xu, Jinwang</au><au>Arnost, Michael</au><au>Choquette, Deborah</au><au>Chen, Guanjing</au><au>Zhou, Jie-Hua</au><au>Yao, Yung-Mae</au><au>Ball, Edward D</au><au>Namchuk, Mark</au><au>Davies, Robert J</au><au>Henkel, Greg</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-01-26</date><risdate>2012</risdate><volume>55</volume><issue>2</issue><spage>725</spage><epage>734</epage><pages>725-734</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K i values of <1 nM and a cellular IC50 between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22221201</pmid><doi>10.1021/jm201198w</doi><tpages>10</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2012-01, Vol.55 (2), p.725-734 |
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| subjects | Animals Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Survival - drug effects fms-Like Tyrosine Kinase 3 - antagonists & inhibitors Humans Leukemia, Myeloid, Acute - drug therapy Male Mice Mice, Inbred BALB C Morpholines - pharmacology Neoplasm Transplantation Proto-Oncogene Proteins c-kit - antagonists & inhibitors Serum Triazoles - pharmacology Tumor Cells, Cultured |
| title | VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia |
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