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KMID : 1140220150200010078
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대한암예방학회지
2015 Volume.20 No. 1 p.78 ~ p.83
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Identification of a New Selective Chemical Inhibitor of Mutant Isocitrate Dehydrogenase-1
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Kim Hyo-Joon
Choi Bu-Young
Keum Young-Sam
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Abstract
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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 α-ketoglutarate (α-KG). In addition, we have observed that IDH1-R132H was more efficient than IDH1 in converting α-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.
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KEYWORD
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Isocitrate dehydrogenase-1, Isocitrate, α-ketoglutarate, (R)-2-hydroxyglutarate, 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one
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