Identification of a New Selective Chemical Inhibitor of Mutant Isocitrate Dehydrogenase-1.
10.15430/JCP.2015.20.1.78
- Author:
Hyo Joon KIM
1
;
Bu Young CHOI
;
Young Sam KEUM
Author Information
1. College of Pharmacy, Dongguk University, Goyang, Seowon University, Cheongju, Korea. keum03@dongguk.edu
- Publication Type:Brief Communication
- Keywords:
Isocitrate dehydrogenase-1;
Isocitrate;
alpha-ketoglutarate;
(R)-2-hydroxyglutarate;
2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one
- MeSH:
Arginine;
Glioma;
Histidine;
Histones;
Humans;
Mutation, Missense
- From:Journal of Cancer Prevention
2015;20(1):78-83
- CountryRepublic of Korea
- Language:English
-
Abstract:
BACKGROUND: Recent genome-wide sequencing studies have identified unexpected genetic alterations in cancer. In particular, missense mutations in isocitrate dehydrogenase-1 (IDH1) at arginine 132, mostly substituted into histidine (IDH1-R132H) were observed to frequently occur in glioma patients. METHODS: We have purified recombinant IDH1 and IDH1-R132H proteins and monitored their catalytic activities. In parallel experiments, we have attempted to find new selective IDH1-R132H chemical inhibitor(s) from a fragment-based chemical library. RESULTS: We have found that IDH1, but not IDH1-R132H, can catalyze the conversion of isocitrate into alpha-ketoglutarate (alpha-KG). In addition, we have observed that IDH1-R132H was more efficient than IDH1 in converting alpha-KG into (R)-2-hydroxyglutarate (R-2HG). Moreover, we have identified a new hit molecule, e.g., 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one as a new selective IDH1-R132H inhibitor. CONCLUSIONS: We have observed an underlying biochemical mechanism explaining how a heterozygous IDH1 mutation contributes to the generation of R-2HG and increases cellular histone H3 trimethylation levels. We have also identified a novel selective IDH1-R132H chemical hit molecule, e.g., 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one, which could be used for a future lead development against IDH1-R132H.
