Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening

Zhe Duan; Jingqiu Liu; Liping Niu; Jun Wang; Mingqian Feng; Hua Chen; Cheng Luo

doi:10.1016/j.bmc.2019.05.040

Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening

Bioorg Med Chem. 2019 Aug 1;27(15):3229-3236. doi: 10.1016/j.bmc.2019.05.040. Epub 2019 May 28.

Authors

Zhe Duan¹, Jingqiu Liu², Liping Niu³, Jun Wang², Mingqian Feng⁴, Hua Chen⁵, Cheng Luo⁶

Affiliations

¹ College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China.
⁴ College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. Electronic address: fengmingqian@mail.hzau.edu.cn.
⁵ Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China. Electronic address: hua-todd@hbu.edu.cn.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: cluo@simm.ac.cn.

PMID: 31208797
DOI: 10.1016/j.bmc.2019.05.040

Abstract

IDH1 mutations are early events in the development of IDH-mutant gliomas and leukemias and are associated with various regulation of molecular process. Mutations of active site in IDH1 could lead to high levels of 2-HG and the suppression of cellular differentiation, while these changes can be reversed by molecule inhibitors target mutant IDH1. Here, through in-house developed enzymatic assay-based high throughput screening platform, we discovered DC_H31 as a novel IDH1-R132H/C inhibitor, with the IC₅₀ value of 0.41 μmol/L and 2.7 μmol/L respectively. In addition, saturable SPR binding assay indicated that DC_H31 bound to IDH1-R132H/C due to specific interaction. Further computational docking studies and structure-activity relationship (SAR) suggest that DC_H31 could occupy the allosteric pocket between the two monomers of IDH1-R132H homodimer, which accounts for its inhibitory ability. And it is possible to conclude that DC_H31 acts via an allosteric mechanism of inhibition. At the cellular level, DC_H31 could inhibit cell proliferation, promote cell differentiation and reduce the production of 2-HG with a dose-dependent manner in HT1080 cells. Taken together, DC_H31 is a potent selective inhibitor of IDH1-R132H/C both in vitro and in vivo, which can promote the development of more potent pan-inhibitors against IDH1-R132H/C through further structural decoration and provide a new insight for the pharmacological treatment of gliomas.

Keywords: 2-HG; Gliomas; High-throughput screening; IDH1 mutation; Pan-inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
High-Throughput Screening Assays*
Humans
Isocitrate Dehydrogenase / antagonists & inhibitors*
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / metabolism
Molecular Structure
Mutation
NADP / metabolism*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
NADP
Isocitrate Dehydrogenase
IDH1 protein, human