Identification of a New Selective Chemical Inhibitor of Mutant Isocitrate Dehydrogenase-1
Journal of Cancer Prevention
;
: 78-83, 2015.
Artículo
en Inglés
| WPRIM
| ID: wpr-173801
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.
Texto completo:
Disponible
Índice:
WPRIM (Pacífico Occidental)
Asunto principal:
Arginina
/
Histonas
/
Mutación Missense
/
Glioma
/
Histidina
Tipo de estudio:
Estudio diagnóstico
Límite:
Humanos
Idioma:
Inglés
Revista:
Journal of Cancer Prevention
Año:
2015
Tipo del documento:
Artículo
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