Structure based discovery of clomifene as a potent inhibitor of cancer-associated mutant IDH1

Oncotarget
Mengzhu ZhengHua Li

Abstract

Isocitrate dehydrogenase (IDH) plays an indispensable role in the tricarboxylic acid cycle, and IDH mutations are present in nearly 75% of glioma and 20% of acute myeloid leukemia. One IDH1R132H inhibitor (clomifene citrate) was found by virtual screening method, which can selectively suppress mutant enzyme activities in vitro and in vivo with a dose-dependent manner. The molecular docking indicated that clomifene occupied the allosteric site of the mutant IDH1. Enzymatic kinetics also demonstrated that clomifene inhibited mutant enzyme in a non-competitive manner. Moreover, knockdown of mutant IDH1 in HT1080 cells decreased the sensitivity to clomifene. In vivo studies indicated that clomifene significantly suppressed the tumor growth of HT1080-bearing CB-17/Icr-scid mice with oral administration of 100 mg/kg and 50 mg/kg per day. In short, our findings highlight clomifene may have clinical potential in tumor therapies as a safe and effective inhibitor of mutant IDH1.

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Dec 29, 2017·International Journal of Molecular Sciences·Joonhyeok ChoiJun-Goo Jee
Apr 5, 2018·Frontiers in Pharmacology·Sze Kiat TanNagi G Ayad
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Methods Mentioned

BETA
X-ray
Microscale thermophoresis
FACS
flow cytometry
xenograft
NMR
size exclusion chromatography

Software Mentioned

SPSS
GraphPad
Graph Pad Prism
NTAnalysis
ICM
Analyst
Prism
Pro
Image J

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