Identification of a novel selective inhibitor of mutant isocitrate dehydrogenase 1 at allosteric site by docking-based virtual screening. Issue 99 (11th October 2016)

• Record Type: Journal Article
• Authors: Zou, Fangxia; Pusch, Stefan; Eisel, Jessica; Ma, Tianfang; Zhu, Qihua; Deng, Dawei; Gu, Yueqing; Xu, Yungen; von Deimling, Andreas; Zha, Xiaoming
• Is Part Of: RSC advances. Volume 6:Issue 99(2016)
• Page Start: 96735
• Page End: 96742
• Publication Date: 2016-10-11
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c6ra21617j
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Optimal docking was employed to screen SPECS compound library, followed by cellular assays of mutant and wild type of IDH1. Abstract : Isocitrate dehydrogenase 1 (IDH1), catalyzing oxidative decarboxylation of isocitrate to provide energy for aerobic organisms, is an essential enzyme in the tricarboxylic acid cycle. However, mutant IDH1 (mIDH1) produces oncometabolited -2-hydroxyglutarate (D2HG) and has recently been confirmed in several types of cancers, particularly in glioma and acute myeloid leukemia. Herein a docking-based virtual screening (VS) of SPECS library was conducted for the allosteric site of mIDH1. The cellular evaluation of the hit compounds led to the identification ofFX-03 as a novel selective mIDH1 inhibitor at allosteric site with IC50 values of 55.50 μM and 68.38 μM in HEK-293T cells transfected with IDH1 R132H and IDH1 R132C, respectively. Importantly, FX-03 owned significant selectivity with no inhibition in HEK-293T cells transfected with IDH1 WT. These findings indicate that VS of mIDH1's allosteric site represents a useful strategy for discovery of selective mIDH1 inhibitors andFX-03 deserves further optimization as a lead compound in future study.