Reference Detail

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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Molecular Profile	Treatment Approach
IDH2 R172G	IDH2 Inhibitor
IDH2 R172M	IDH2 Inhibitor
IDH2 R172S	IDH2 Inhibitor
IDH2 R172K	IDH2 Inhibitor
IDH2 R172W	IDH2 Inhibitor
IDH2 act mut	IDH2 Inhibitor
IDH2 R140X	IDH2 Inhibitor
IDH2 R172X	IDH2 Inhibitor
IDH2 R140G	IDH2 Inhibitor
IDH2 R140W	IDH2 Inhibitor
IDH2 R140L	IDH2 Inhibitor
IDH2 R140Q	IDH2 Inhibitor

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	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 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	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
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