Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity
Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-10, Vol.57 (20), p.8307-8318 |
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| creator | Liu, Zhen Yao, Yuan Kogiso, Mari Zheng, Baisong Deng, Lisheng Qiu, Jihui J Dong, Shuo Lv, Hua Gallo, James M Li, Xiao-Nan Song, Yongcheng |
| description | Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure–activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with K i values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R 2 of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood–brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26–1.8 μM) against glioma cells with the IDH1 R132H mutation. |
| doi_str_mv | 10.1021/jm500660f |
| format | Article |
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Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure–activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with K i values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R 2 of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood–brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26–1.8 μM) against glioma cells with the IDH1 R132H mutation.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm500660f</identifier><identifier>PMID: 25271760</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Blood-Brain Barrier - drug effects ; Brain Neoplasms - drug therapy ; Brain Neoplasms - pathology ; Crystallography, X-Ray ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Glioma - drug therapy ; Glioma - pathology ; Glutarates - metabolism ; Humans ; Isocitrate Dehydrogenase - antagonists & inhibitors ; Isocitrate Dehydrogenase - genetics ; Mice ; Pyridones - chemistry ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of medicinal chemistry, 2014-10, Vol.57 (20), p.8307-8318</ispartof><rights>Copyright © 2014 American Chemical Society</rights><rights>Copyright © 2014 American Chemical Society 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a471t-53f26f608c8916a7727b355ca605c028fa7b0fc361180c173a4a072a262f8e8a3</citedby><cites>FETCH-LOGICAL-a471t-53f26f608c8916a7727b355ca605c028fa7b0fc361180c173a4a072a262f8e8a3</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/jm500660f$$EPDF$$P50$$Gacs$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm500660f$$EHTML$$P50$$Gacs$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25271760$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Zhen</creatorcontrib><creatorcontrib>Yao, Yuan</creatorcontrib><creatorcontrib>Kogiso, Mari</creatorcontrib><creatorcontrib>Zheng, Baisong</creatorcontrib><creatorcontrib>Deng, Lisheng</creatorcontrib><creatorcontrib>Qiu, Jihui J</creatorcontrib><creatorcontrib>Dong, Shuo</creatorcontrib><creatorcontrib>Lv, Hua</creatorcontrib><creatorcontrib>Gallo, James M</creatorcontrib><creatorcontrib>Li, Xiao-Nan</creatorcontrib><creatorcontrib>Song, Yongcheng</creatorcontrib><title>Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure–activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with K i values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R 2 of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood–brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26–1.8 μM) against glioma cells with the IDH1 R132H mutation.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - pathology</subject><subject>Crystallography, X-Ray</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Glioma - drug therapy</subject><subject>Glioma - pathology</subject><subject>Glutarates - metabolism</subject><subject>Humans</subject><subject>Isocitrate Dehydrogenase - antagonists & inhibitors</subject><subject>Isocitrate Dehydrogenase - genetics</subject><subject>Mice</subject><subject>Pyridones - chemistry</subject><subject>Structure-Activity Relationship</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>N~.</sourceid><sourceid>EIF</sourceid><recordid>eNptkc-KFDEQh4Mo7uzqwReQXASFba2ku5NeD8Iw_htYERw9h5pMsp2hO5lN0gtz20cQfEOfxG5md1DwFKj6-CpVP0KeMXjNgLM3274GEALsAzJjNYeiaqB6SGYAnBdc8PKEnKa0BYCS8fIxOeE1l0wKmJGfS9-6tcsueBosXaDXJhbzlIJ2mM2Gfhky-kyXUyHHsUTfm3a_ieHKeEwmvaWrvc-tSS6d01WOg85DNL9vf811djcu7-k30-HkT63bnVP0G7oynZm6hs59dnnoQ6T3-BPyyGKXzNO794z8-Pjh--Jzcfn103IxvyywkiwXdWm5sAIa3VwwgVJyuS7rWqOAWgNvLMo1WF0KxhrQTJZYIUiO4zVsYxosz8i7g3c3rHuz0caP23VqF12Pca8COvVvx7tWXYUbVXGQdQWj4OWdIIbrwaSsepe06Tr0JgxJMcFEJcWFmNBXB1THkFI09jiGgZoSVMcER_b53_86kveRjcCLA4A6qW0Yoh_P9B_RHw7cpuQ</recordid><startdate>20141023</startdate><enddate>20141023</enddate><creator>Liu, Zhen</creator><creator>Yao, Yuan</creator><creator>Kogiso, Mari</creator><creator>Zheng, Baisong</creator><creator>Deng, Lisheng</creator><creator>Qiu, Jihui J</creator><creator>Dong, Shuo</creator><creator>Lv, Hua</creator><creator>Gallo, James M</creator><creator>Li, Xiao-Nan</creator><creator>Song, Yongcheng</creator><general>American Chemical Society</general><scope>N~.</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>20141023</creationdate><title>Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity</title><author>Liu, Zhen ; Yao, Yuan ; Kogiso, Mari ; Zheng, Baisong ; Deng, Lisheng ; Qiu, Jihui J ; Dong, Shuo ; Lv, Hua ; Gallo, James M ; Li, Xiao-Nan ; Song, Yongcheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a471t-53f26f608c8916a7727b355ca605c028fa7b0fc361180c173a4a072a262f8e8a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Blood-Brain Barrier - drug effects</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - pathology</topic><topic>Crystallography, X-Ray</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Glioma - drug therapy</topic><topic>Glioma - pathology</topic><topic>Glutarates - metabolism</topic><topic>Humans</topic><topic>Isocitrate Dehydrogenase - antagonists & inhibitors</topic><topic>Isocitrate Dehydrogenase - genetics</topic><topic>Mice</topic><topic>Pyridones - chemistry</topic><topic>Structure-Activity Relationship</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Zhen</creatorcontrib><creatorcontrib>Yao, Yuan</creatorcontrib><creatorcontrib>Kogiso, Mari</creatorcontrib><creatorcontrib>Zheng, Baisong</creatorcontrib><creatorcontrib>Deng, Lisheng</creatorcontrib><creatorcontrib>Qiu, Jihui J</creatorcontrib><creatorcontrib>Dong, Shuo</creatorcontrib><creatorcontrib>Lv, Hua</creatorcontrib><creatorcontrib>Gallo, James M</creatorcontrib><creatorcontrib>Li, Xiao-Nan</creatorcontrib><creatorcontrib>Song, Yongcheng</creatorcontrib><collection>American Chemical Society (ACS) Open Access</collection><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><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>Liu, Zhen</au><au>Yao, Yuan</au><au>Kogiso, Mari</au><au>Zheng, Baisong</au><au>Deng, Lisheng</au><au>Qiu, Jihui J</au><au>Dong, Shuo</au><au>Lv, Hua</au><au>Gallo, James M</au><au>Li, Xiao-Nan</au><au>Song, Yongcheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2014-10-23</date><risdate>2014</risdate><volume>57</volume><issue>20</issue><spage>8307</spage><epage>8318</epage><pages>8307-8318</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure–activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with K i values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R 2 of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood–brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26–1.8 μM) against glioma cells with the IDH1 R132H mutation.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25271760</pmid><doi>10.1021/jm500660f</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Blood-Brain Barrier - drug effects Brain Neoplasms - drug therapy Brain Neoplasms - pathology Crystallography, X-Ray Drug Screening Assays, Antitumor Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Glioma - drug therapy Glioma - pathology Glutarates - metabolism Humans Isocitrate Dehydrogenase - antagonists & inhibitors Isocitrate Dehydrogenase - genetics Mice Pyridones - chemistry Structure-Activity Relationship Xenograft Model Antitumor Assays |
| title | Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity |
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