J Cancer Prev.  2015 Mar;20(1):78-83. 10.15430/JCP.2015.20.1.78.

Identification of a New Selective Chemical Inhibitor of Mutant Isocitrate Dehydrogenase-1

• Kim HJ
• Choi BY
• Keum YS

• KMID: 2171321
• DOI: http://doi.org/10.15430/JCP.2015.20.1.78

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.

Keyword

Isocitrate dehydrogenase-1; Isocitrate; alpha-ketoglutarate; (R)-2-hydroxyglutarate; 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one

MeSH Terms

Arginine
Glioma
Histidine
Histones
Humans
Mutation, Missense
Arginine
Histidine
Histones