Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants
文献类型：期刊论文
| 作者 | Gao, Mingzhao1,2; Zhu, Hongmei1,2; Fu, Li1; Li, Yun1; Bao, Xubin1; Fu, Haoyu1; Quan, Haitian1 ; Wang, Lei1; Lou, Liguang1
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| 刊名 | CANCER SCIENCE
 |
| 出版日期 | 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. |
| WOS关键词 | IDH MUTATIONS ; ONCOMETABOLITE 2-HYDROXYGLUTARATE ; PROGNOSTIC-SIGNIFICANCE ; (R)-2-HYDROXYGLUTARATE ; LEUKEMIA ; GLIOMA ; CELLS ; BLOCK |
| 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研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000481954100001 |
| 出版者 | WILEY |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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