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Ref Type Journal Article
PMID (31361380)
Authors Gao M, Zhu H, Fu L, Li Y, Bao X, Fu H, Quan H, Wang L, Lou L
Title Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants.
Journal Cancer science
Vol 110
Issue 10
Date 2019 Oct
URL
Abstract Text Isocitrate dehydrogenase 2 (IDH2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. AG-221, an inhibitor primarily targeting the IDH2-R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, AG-221 has weak inhibitory activity toward IDH2-R172K, a mutant form of IDH2 with more severe clinical manifestations. Herein, we report TQ05310 as the first mutant IDH2 inhibitor that potently targets both IDH2-R140Q and IDH2-R172K mutants. TQ05310 inhibited mutant IDH2 enzymatic activity, suppressed (R)-2-hydroxyglutarate (2-HG) production and induced differentiation in cells expressing IDH2-R140Q and IDH2-R172K, but not in cells expressing wild-type IDH1/2 or mutant IDH1. TQ05310 bound to both IDH2-R140Q and IDH2-R172K, with Q316 being the critical residue mediating the binding of TQ05310 with IDH2-R140Q, but not with IDH2-R172K. TQ05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2-HG production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of TQ05310, and provide new insight into the development of novel mutant IDH2 inhibitors.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
TQ05310 IDH2 Inhibitor 5 TQ05310 inhibits IDH2, potentially resulting in increased differentiation and decreased proliferation of tumor cells (PMID: 31361380).
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 TQ05310 Preclinical - Cell culture Actionable In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in an acute myeloid leukemia cell line expressing IDH2 R172K in culture (PMID: 31361380). 31361380
IDH2 R140Q acute myeloid leukemia sensitive TQ05310 Preclinical - Cell culture Actionable In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in an acute myeloid leukemia cell line expressing IDH2 R140Q in culture (PMID: 31361380). 31361380
IDH2 R140Q high grade glioma sensitive TQ05310 Preclinical - Cell culture Actionable In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in a glioma cell line expressing IDH2 R140Q in culture (PMID: 31361380). 31361380
IDH2 R172K high grade glioma sensitive TQ05310 Preclinical - Cell culture Actionable In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in a glioma cell line expressing IDH2 R172K in culture (PMID: 31361380). 31361380