Reference Detail

Ref Type

Journal Article

PMID

(23558169)

Authors

Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK

Title

An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science (New York, N.Y.)	340	6132	2013 May 3	626-30	Science

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach
IDH1 R132G	IDH1 Inhibitor

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AGI-5198	AGI-5198	4	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AGI-5198		AG5198\|AGI 5198\|IDH-C35	IDH1 Inhibitor 8	AGI-5198 is a selective inhibitor of mutant forms of IDH1, which decreases production of R-2HG, potentially leading to reduced growth of IDH1-mutant tumor cells (PMID: 23558169, PMID: 26368816, PMID: 31151327).

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
IDH1 R132H	high grade glioma	sensitive	AGI-5198	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AGI-5198 inhibited growth of a glioma cell line harboring IDH1 R132H in culture and in xenograft models (PMID: 23558169).	23558169
IDH1 R132C	high grade glioma	sensitive	AGI-5198	Preclinical	Actionable	In a preclinical study, AGI-5198 inhibited growth and promoted differentiation in glioma cells expressing IDH1 R132C (PMID: 23558169).	23558169