Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants

doi:10.1111/cas.14152

	Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants
	Gao, Mingzhao 1,2; Zhu, Hongmei 1,2; Fu, Li 1; Li, Yun 1; Bao, Xubin 1; Fu, Haoyu 1; Quan, Haitian 1; Wang, Lei 1; Lou, Liguang 1
刊名	CANCER SCIENCE
	2019-08-20
页码	9
关键词	AG-221 IDH2 leukemia R140Q R172K
ISSN号	1347-9032
DOI	10.1111/cas.14152
通讯作者	Wang, Lei(wanglei@simm.ac.cn) ; Lou, Liguang(lglou@mail.shcnc.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81502636] ; Yunnan Provincial Science and Technology Department[2017ZF010] ; Science and Technology Commission of Shanghai Municipality[14DZ2294100]
WOS关键词	IDH MUTATIONS ; ONCOMETABOLITE 2-HYDROXYGLUTARATE ; PROGNOSTIC-SIGNIFICANCE ; (R)-2-HYDROXYGLUTARATE ; LEUKEMIA ; GLIOMA ; CELLS ; BLOCK
WOS研究方向	Oncology
语种	英语
出版者	WILEY
WOS记录号	WOS:000481954100001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288857]
专题	中国科学院上海药物研究所
通讯作者	Wang, Lei; Lou, Liguang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Gao, Mingzhao,Zhu, Hongmei,Fu, Li,et al. Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants[J]. CANCER SCIENCE,2019:9.
APA	Gao, Mingzhao.,Zhu, Hongmei.,Fu, Li.,Li, Yun.,Bao, Xubin.,...&Lou, Liguang.(2019).Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants.CANCER SCIENCE,9.
MLA	Gao, Mingzhao,et al."Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants".CANCER SCIENCE (2019):9.