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Ref Type Journal Article
PMID (23558173)
Authors Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, Yen KE
Title Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.
Journal Science (New York, N.Y.)
Vol 340
Issue 6132
Date 2013 May 3
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AGI-6780 AGI-6780 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
AGI-6780 AGI6780 IDH2 Inhibitor 2 AGI-6780 inhibits mutant IDH2, potentially resulting in increased differentiation and decreased growth of cancer cells harboring IDH2 mutations (PMID: 23558173, PMID: 28986582, PMID: 30455381).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
IDH2 R140Q missense gain of function IDH2 R140Q lies within the substrate binding region of the Idh2 protein (UniProt.org). R140Q confers a gain of function to Idh2, enabling conversion of alpha-ketoglutarate to the onco-metabolite 2HG (R(-)-2-hydroxyglutarate), results in increased 2HG levels in patient samples, and is transforming in cell culture (PMID: 20171147, PMID: 23558173).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH2 R140Q acute myeloid leukemia sensitive AGI-6780 Preclinical Actionable In a preclinical study, treatment with AGI-6780 resulted in the differentiation of erythroleukemia and AML cell lines expressing IDH2 R140Q (PMID: 23558173). 23558173