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  • 1
    Publication Date: 2013-04-06
    Description: The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant--but not IDH1-wild-type--glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985613/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985613/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rohle, Dan -- Popovici-Muller, Janeta -- Palaskas, Nicolaos -- Turcan, Sevin -- Grommes, Christian -- Campos, Carl -- Tsoi, Jennifer -- Clark, Owen -- Oldrini, Barbara -- Komisopoulou, Evangelia -- Kunii, Kaiko -- Pedraza, Alicia -- Schalm, Stefanie -- Silverman, Lee -- Miller, Alexandra -- Wang, Fang -- Yang, Hua -- Chen, Yue -- Kernytsky, Andrew -- Rosenblum, Marc K -- Liu, Wei -- Biller, Scott A -- Su, Shinsan M -- Brennan, Cameron W -- Chan, Timothy A -- Graeber, Thomas G -- Yen, Katharine E -- Mellinghoff, Ingo K -- 1R01NS080944-01/NS/NINDS NIH HHS/ -- R01 NS080944/NS/NINDS NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2013 May 3;340(6132):626-30. doi: 10.1126/science.1236062. Epub 2013 Apr 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23558169" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzeneacetamides/administration & dosage/*pharmacology/toxicity ; *Cell Differentiation/drug effects ; Cell Transformation, Neoplastic ; Enzyme Inhibitors/*pharmacology/toxicity ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Glioma/drug therapy/*enzymology/genetics/*pathology ; Glutarates/metabolism ; Histones/metabolism ; Imidazoles/administration & dosage/*pharmacology/toxicity ; Isocitrate Dehydrogenase/*antagonists & inhibitors/chemistry/*genetics/metabolism ; Methylation ; Mice ; Mice, SCID ; Mutant Proteins/antagonists & inhibitors/chemistry/metabolism ; Protein Multimerization ; RNA Interference ; Xenograft Model Antitumor Assays
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-04-06
    Description: A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Fang -- Travins, Jeremy -- DeLaBarre, Byron -- Penard-Lacronique, Virginie -- Schalm, Stefanie -- Hansen, Erica -- Straley, Kimberly -- Kernytsky, Andrew -- Liu, Wei -- Gliser, Camelia -- Yang, Hua -- Gross, Stefan -- Artin, Erin -- Saada, Veronique -- Mylonas, Elena -- Quivoron, Cyril -- Popovici-Muller, Janeta -- Saunders, Jeffrey O -- Salituro, Francesco G -- Yan, Shunqi -- Murray, Stuart -- Wei, Wentao -- Gao, Yi -- Dang, Lenny -- Dorsch, Marion -- Agresta, Sam -- Schenkein, David P -- Biller, Scott A -- Su, Shinsan M -- de Botton, Stephane -- Yen, Katharine E -- New York, N.Y. -- Science. 2013 May 3;340(6132):622-6. doi: 10.1126/science.1234769. Epub 2013 Apr 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Agios Pharmaceuticals, Cambridge, MA 02139-4169, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23558173" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Site ; Antineoplastic Agents/chemistry/metabolism/pharmacology ; Catalytic Domain ; Cell Line, Tumor ; Cell Proliferation ; Cells, Cultured ; Crystallography, X-Ray ; Enzyme Inhibitors/chemistry/metabolism/*pharmacology ; Erythropoiesis/drug effects ; Gene Expression Regulation, Leukemic ; Glutarates/metabolism ; Hematopoiesis/*drug effects ; Humans ; Isocitrate Dehydrogenase/*antagonists & inhibitors/chemistry/*genetics/metabolism ; Leukemia, Erythroblastic, Acute ; Leukemia, Myeloid, Acute/drug therapy/*enzymology/genetics/pathology ; Molecular Targeted Therapy ; Mutant Proteins/antagonists & inhibitors/chemistry/metabolism ; Phenylurea Compounds/chemistry/metabolism/*pharmacology ; Point Mutation ; Protein Multimerization ; Protein Structure, Secondary ; Small Molecule Libraries ; Sulfonamides/chemistry/metabolism/*pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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