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Ref Type Journal Article
PMID (28193778)
Authors Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, Chen Y, Nagaraja R, Choe S, Jin L, Konteatis Z, Cianchetta G, Saunders JO, Salituro FG, Quivoron C, Opolon P, Bawa O, Saada V, Paci A, Broutin S, Bernard OA, de Botton S, Marteyn BS, Pilichowska M, Xu Y, Fang C, Jiang F, Wei W, Jin S, Silverman L, Liu W, Yang H, Dang L, Dorsch M, Penard-Lacronique V, Biller SA, Su SM
Title AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 7 5 2017 05 478-493 Cancer Discov
URL
Abstract Text Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies.Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478-93. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Shih et al., p. 494This article is highlighted in the In This Issue feature, p. 443.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH2 R172K acute myeloid leukemia sensitive Enasidenib Preclinical - Patient cell culture Actionable In a preclinical study, Enasidenib (AG-221) decreased 2-hydroxyglutarate (2HG) levels and induced differentiation of leukemic blasts from acute myeloid leukemia (AML) patients harboring IDH2 R172K in culture (PMID: 28193778). 28193778
IDH2 R140Q glioblastoma predicted - sensitive Enasidenib Preclinical - Cell line xenograft Actionable In a preclinical study, Enasidenib (AG-221) decreased 2-hydroxyglutarate (2HG) levels in a glioblastoma cell line expressing IDH2 R140Q in culture and in xenograft models (PMID: 28193778). 28193778
IDH2 R172K colorectal cancer predicted - sensitive Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Enasidenib (AG-221) decreased 2-hydroxyglutarate (2HG) levels in a colorectal carcinoma cell line expressing IDH2 R172K in culture (PMID: 28193778). 28193778
IDH2 R140Q acute myeloid leukemia sensitive Enasidenib Preclinical - Pdx & cell culture Actionable In a preclinical study, Enasidenib (AG-221) treatment reduced 2-hydroxyglutarate (2HG) levels and induced differentiation of leukemic blasts from acute myeloid leukemia (AML) patients harboring IDH2 R140Q in culture, and decreased 2HG levels and blast percentage and improved survival relative to Cytosar-U (cytarabine) treatment in IDH2 R140Q-mutant primary AML xenograft models (PMID: 28193778). 28193778
IDH2 R172K glioblastoma predicted - sensitive Enasidenib Preclinical - Biochemical Actionable In a preclinical study, Enasidenib (AG-221) decreased 2-hydroxyglutarate (2HG) levels in a glioblastoma cell line expressing IDH2 R172K in culture (PMID: 28193778). 28193778