Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer science	110	10	2019 Oct	3306-3314	Cancer Sci

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
TQ05310	TQ05310	4	0

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	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
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 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 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