Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase
详细信息 查看全文
- 作者：Baisong Zheng ; Yuan Yao ; Zhen Liu ; Lisheng Deng ; Justin L. Anglin ; Hong Jiang ; B. V. Venkataram Prasad ; Yongcheng Song
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：June 13, 2013
- 年：2013
- 卷：4
- 期：6
- 页码：542-546
- 全文大小：297K
- 年卷期：v.4,no.6(June 13, 2013)
- ISSN：1948-5875
文摘
Mutations in isocitrate dehydrogenase (IDH), a key enzyme in the tricarboxylic acid cycle, have recently been found in 75% glioma and 20% acute myeloid leukemia. Different from the wild-type enzyme, mutant IDH1 catalyzes the reduction of 伪-ketoglutaric acid to d-2-hydroxyglutaric acid. Strong evidence has shown mutant IDH1 represents a novel target for this type of cancer. We found two 1-hydroxypyridin-2-one compounds that are potent inhibitors of R132H and R132C IDH1 mutants with Ki values as low as 120 nM. These compounds exhibit >60-fold selectivity against wild-type IDH1 and can inhibit the production of d-2-hydroxyglutaric acid in IDH1 mutated cells, representing novel chemical probes for cancer biology studies. We also report the first inhibitor-bound crystal structures of IDH1(R132H), showing these inhibitors have H-bond, electrostatic, and hydrophobic interactions with the mutant enzyme. Comparison with the substrate-bound IDH1 structures revealed the structural basis for the high enzyme selectivity of these compounds.