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 s...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
26 Sep 2016
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| In: |
RSC Advances
Year: 2016, Volume: 6, Issue: 99, Pages: 96735-96742 |
| ISSN: | 2046-2069 |
| DOI: | 10.1039/C6RA21617J |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1039/C6RA21617J Verlag, Volltext: https://pubs.rsc.org/en/content/articlelanding/2016/ra/c6ra21617j 
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| Author Notes: | Fangxia Zou, Stefan Pusch, Jessica Eisel, Tianfang Ma, Qihua Zhu, Dawei Deng, Yueqing Gu, Yungen Xu, Andreas von Deimling and Xiaoming Zha |
| 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 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 and FX-03 deserves further optimization as a lead compound in future study. |
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| Item Description: | Gesehen am 10.12.2019 |
| Physical Description: | Online Resource |
| ISSN: | 2046-2069 |
| DOI: | 10.1039/C6RA21617J |