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Identification of (R)‑N‑((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)‑1H‑indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B‑Cell Lymphomas
Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 co...
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| Published in: | Journal of medicinal chemistry 2016-11, Vol.59 (21), p.9928-9941 |
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| container_end_page | 9941 |
| container_issue | 21 |
| container_start_page | 9928 |
| container_title | Journal of medicinal chemistry |
| container_volume | 59 |
| creator | Vaswani, Rishi G Gehling, Victor S Dakin, Les A Cook, Andrew S Nasveschuk, Christopher G Duplessis, Martin Iyer, Priyadarshini Balasubramanian, Srividya Zhao, Feng Good, Andrew C Campbell, Robert Lee, Christina Cantone, Nico Cummings, Richard T Normant, Emmanuel Bellon, Steven F Albrecht, Brian K Harmange, Jean-Christophe Trojer, Patrick Audia, James E Zhang, Ying Justin, Neil Chen, Shuyang Wilson, Jon R Gamblin, Steven J |
| description | Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 μM, cellular EC50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex. |
| doi_str_mv | 10.1021/acs.jmedchem.6b01315 |
| format | article |
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Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 μM, cellular EC50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.6b01315</identifier><identifier>PMID: 27739677</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Proliferation - drug effects ; Clinical Trials, Phase I as Topic ; Dogs ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Histone Methyltransferases ; Histone-Lysine N-Methyltransferase - antagonists & inhibitors ; Histone-Lysine N-Methyltransferase - metabolism ; Humans ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; Lymphoma, B-Cell - drug therapy ; Models, Molecular ; Molecular Structure ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - pathology ; Piperidines - chemical synthesis ; Piperidines - chemistry ; Piperidines - pharmacology ; Rats ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2016-11, Vol.59 (21), p.9928-9941</ispartof><rights>Copyright © 2016 American Chemical Society</rights><rights>Copyright © 2016 American Chemical Society 2016 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27739677$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vaswani, Rishi G</creatorcontrib><creatorcontrib>Gehling, Victor S</creatorcontrib><creatorcontrib>Dakin, Les A</creatorcontrib><creatorcontrib>Cook, Andrew S</creatorcontrib><creatorcontrib>Nasveschuk, Christopher G</creatorcontrib><creatorcontrib>Duplessis, Martin</creatorcontrib><creatorcontrib>Iyer, Priyadarshini</creatorcontrib><creatorcontrib>Balasubramanian, Srividya</creatorcontrib><creatorcontrib>Zhao, Feng</creatorcontrib><creatorcontrib>Good, Andrew C</creatorcontrib><creatorcontrib>Campbell, Robert</creatorcontrib><creatorcontrib>Lee, Christina</creatorcontrib><creatorcontrib>Cantone, Nico</creatorcontrib><creatorcontrib>Cummings, Richard T</creatorcontrib><creatorcontrib>Normant, Emmanuel</creatorcontrib><creatorcontrib>Bellon, Steven F</creatorcontrib><creatorcontrib>Albrecht, Brian K</creatorcontrib><creatorcontrib>Harmange, Jean-Christophe</creatorcontrib><creatorcontrib>Trojer, Patrick</creatorcontrib><creatorcontrib>Audia, James E</creatorcontrib><creatorcontrib>Zhang, Ying</creatorcontrib><creatorcontrib>Justin, Neil</creatorcontrib><creatorcontrib>Chen, Shuyang</creatorcontrib><creatorcontrib>Wilson, Jon R</creatorcontrib><creatorcontrib>Gamblin, Steven J</creatorcontrib><title>Identification of (R)‑N‑((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)‑1H‑indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B‑Cell Lymphomas</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 μM, cellular EC50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Proliferation - drug effects</subject><subject>Clinical Trials, Phase I as Topic</subject><subject>Dogs</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Histone Methyltransferases</subject><subject>Histone-Lysine N-Methyltransferase - antagonists & inhibitors</subject><subject>Histone-Lysine N-Methyltransferase - metabolism</subject><subject>Humans</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Lymphoma, B-Cell - drug therapy</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Piperidines - chemical synthesis</subject><subject>Piperidines - chemistry</subject><subject>Piperidines - pharmacology</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNpVUtuO0zAQDQjElsIfIOTHVKqLr0kqJCSoFlqpCxW7vPBiObFNXCVxcNJV88Yv8It8CW5TEMhXec6cmfGcKHqB0QIjgl_Jolvsa62KUteLJEeYYv4wmmBOEGQZYo-iCUKEQJIQehU97bo9QohiQp9EVyRN6TJJ08mD1xulm94aW8jeugY4A-LPs18_fn4MK44ZvNF96Y4DTGAdbkMFCXRHB_GcQGXLQXnXDt4q20AKh2o2gmYBdYFjGI-TzMOAvbemOjjvRlxrWz16s5P3-Bgi43XYbKNcpQNvIX3ujrK2SoN4tdtATBCfzYEEO9eH9IFsFLjVlS56e6_BpiltbnvnT9Wsbde7RoObM3fvZdMZ7WWnwfXXNZmD24PtZV5pYAJ-V54MG7CqbBN-pAJ33sqqO9vehYxWuqrAdqjb0tWyexY9NsGqn1_OafTl_fXdag23nz5sVm-3UDK87KFRebFc5llRZMZwlmYSSa4zgxUnqTGUZ0RSqkJHNJMJTzKWJ4gSijhNmWKKTqM3I297yE8NDxV7WYnW21r6QThpxf-Wxpbim7sXnHGMOQoE8YXAu-8H3fWitl0RapGNdodO4IxyhlMWxDGNXv4b62-QP4oJADQCgv7E3h18E0oXGImTKMX58SJKcREl_Q1yhNsZ</recordid><startdate>20161110</startdate><enddate>20161110</enddate><creator>Vaswani, Rishi G</creator><creator>Gehling, Victor S</creator><creator>Dakin, Les A</creator><creator>Cook, Andrew S</creator><creator>Nasveschuk, Christopher G</creator><creator>Duplessis, Martin</creator><creator>Iyer, Priyadarshini</creator><creator>Balasubramanian, Srividya</creator><creator>Zhao, Feng</creator><creator>Good, Andrew C</creator><creator>Campbell, Robert</creator><creator>Lee, Christina</creator><creator>Cantone, Nico</creator><creator>Cummings, Richard T</creator><creator>Normant, Emmanuel</creator><creator>Bellon, Steven F</creator><creator>Albrecht, Brian K</creator><creator>Harmange, Jean-Christophe</creator><creator>Trojer, Patrick</creator><creator>Audia, James E</creator><creator>Zhang, Ying</creator><creator>Justin, Neil</creator><creator>Chen, Shuyang</creator><creator>Wilson, Jon R</creator><creator>Gamblin, Steven J</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20161110</creationdate><title>Identification of (R)‑N‑((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)‑1H‑indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B‑Cell Lymphomas</title><author>Vaswani, Rishi G ; Gehling, Victor S ; Dakin, Les A ; Cook, Andrew S ; Nasveschuk, Christopher G ; Duplessis, Martin ; Iyer, Priyadarshini ; Balasubramanian, Srividya ; Zhao, Feng ; Good, Andrew C ; Campbell, Robert ; Lee, Christina ; Cantone, Nico ; Cummings, Richard T ; Normant, Emmanuel ; Bellon, Steven F ; Albrecht, Brian K ; Harmange, Jean-Christophe ; Trojer, Patrick ; Audia, James E ; Zhang, Ying ; Justin, Neil ; Chen, Shuyang ; Wilson, Jon R ; Gamblin, Steven J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a419t-fdbc99b8cc8ff5478a0a5e8f1d527ff3582a33d739e4a65684b6032305374d4d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Proliferation - drug effects</topic><topic>Clinical Trials, Phase I as Topic</topic><topic>Dogs</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Histone Methyltransferases</topic><topic>Histone-Lysine N-Methyltransferase - antagonists & inhibitors</topic><topic>Histone-Lysine N-Methyltransferase - metabolism</topic><topic>Humans</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Lymphoma, B-Cell - drug therapy</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Piperidines - chemical synthesis</topic><topic>Piperidines - chemistry</topic><topic>Piperidines - pharmacology</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vaswani, Rishi G</creatorcontrib><creatorcontrib>Gehling, Victor S</creatorcontrib><creatorcontrib>Dakin, Les A</creatorcontrib><creatorcontrib>Cook, Andrew S</creatorcontrib><creatorcontrib>Nasveschuk, Christopher G</creatorcontrib><creatorcontrib>Duplessis, Martin</creatorcontrib><creatorcontrib>Iyer, Priyadarshini</creatorcontrib><creatorcontrib>Balasubramanian, Srividya</creatorcontrib><creatorcontrib>Zhao, Feng</creatorcontrib><creatorcontrib>Good, Andrew C</creatorcontrib><creatorcontrib>Campbell, Robert</creatorcontrib><creatorcontrib>Lee, Christina</creatorcontrib><creatorcontrib>Cantone, Nico</creatorcontrib><creatorcontrib>Cummings, Richard T</creatorcontrib><creatorcontrib>Normant, Emmanuel</creatorcontrib><creatorcontrib>Bellon, Steven F</creatorcontrib><creatorcontrib>Albrecht, Brian K</creatorcontrib><creatorcontrib>Harmange, Jean-Christophe</creatorcontrib><creatorcontrib>Trojer, Patrick</creatorcontrib><creatorcontrib>Audia, James E</creatorcontrib><creatorcontrib>Zhang, Ying</creatorcontrib><creatorcontrib>Justin, Neil</creatorcontrib><creatorcontrib>Chen, Shuyang</creatorcontrib><creatorcontrib>Wilson, Jon R</creatorcontrib><creatorcontrib>Gamblin, Steven J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vaswani, Rishi G</au><au>Gehling, Victor S</au><au>Dakin, Les A</au><au>Cook, Andrew S</au><au>Nasveschuk, Christopher G</au><au>Duplessis, Martin</au><au>Iyer, Priyadarshini</au><au>Balasubramanian, Srividya</au><au>Zhao, Feng</au><au>Good, Andrew C</au><au>Campbell, Robert</au><au>Lee, Christina</au><au>Cantone, Nico</au><au>Cummings, Richard T</au><au>Normant, Emmanuel</au><au>Bellon, Steven F</au><au>Albrecht, Brian K</au><au>Harmange, Jean-Christophe</au><au>Trojer, Patrick</au><au>Audia, James E</au><au>Zhang, Ying</au><au>Justin, Neil</au><au>Chen, Shuyang</au><au>Wilson, Jon R</au><au>Gamblin, Steven J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of (R)‑N‑((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)‑1H‑indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B‑Cell Lymphomas</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2016-11-10</date><risdate>2016</risdate><volume>59</volume><issue>21</issue><spage>9928</spage><epage>9941</epage><pages>9928-9941</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 μM, cellular EC50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27739677</pmid><doi>10.1021/acs.jmedchem.6b01315</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2016-11, Vol.59 (21), p.9928-9941 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Proliferation - drug effects Clinical Trials, Phase I as Topic Dogs Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Histone Methyltransferases Histone-Lysine N-Methyltransferase - antagonists & inhibitors Histone-Lysine N-Methyltransferase - metabolism Humans Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Lymphoma, B-Cell - drug therapy Models, Molecular Molecular Structure Neoplasms, Experimental - drug therapy Neoplasms, Experimental - pathology Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacology Rats Structure-Activity Relationship |
| title | Identification of (R)‑N‑((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)‑1H‑indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B‑Cell Lymphomas |
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