Identification of a novel selective inhibitor of mutant isocitrate dehydrogenase 1 at allosteric site by docking-based virtual screening

• Verfasst von: Zou, Fangxia [VerfasserIn]
• Verfasst von: Pusch, Stefan [VerfasserIn]
• Verfasst von: Deimling, Andreas von [VerfasserIn]
• Titel: Identification of a novel selective inhibitor of mutant isocitrate dehydrogenase 1 at allosteric site by docking-based virtual screening
• Verf.angabe: Fangxia Zou, Stefan Pusch, Jessica Eisel, Tianfang Ma, Qihua Zhu, Dawei Deng, Yueqing Gu, Yungen Xu, Andreas von Deimling and Xiaoming Zha
• E-Jahr: 2016
• Jahr: 26 Sep 2016
• Umfang: 8 S.
• Fussnoten: Gesehen am 10.12.2019
• Titel Quelle: Enthalten in: Royal Society of ChemistryRSC Advances
• Ort Quelle: London : RSC Publishing, 2011
• Jahr Quelle: 2016
• Band/Heft Quelle: 6(2016), 99, Seite 96735-96742
• ISSN Quelle: 2046-2069
• DOI: doi:10.1039/C6RA21617J
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1580369200

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 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.