Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Science (New York, N.Y.)	340	6132	2013 May 3	622-6	Science

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 5	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