Identification of a novel selective inhibitor of mutant isocitrate dehydrogenase 1 at allosteric site by docking-based virtual screening
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 oncometabolite d -2-hydroxyglutarate (D2HG) and has recently been confirmed in...
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Published in | RSC advances Vol. 6; no. 99; pp. 96735 - 96742 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
2016
|
Online Access | Get full text |
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Summary: | 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 oncometabolite
d
-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 of
FX-03
as a novel selective mIDH1 inhibitor at allosteric site with IC
50
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 and
FX-03
deserves further optimization as a lead compound in future study. |
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ISSN: | 2046-2069 2046-2069 |
DOI: | 10.1039/C6RA21617J |