title: Identification of a new selective chemical inhibitor of mutant isocitrate dehydrogenase-1.
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 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.
authors: College of Pharmacy, Dongguk University, Goyang, Seowon University, Cheongju, Korea.
authors: Hyo-Joon
authors: HJ
authors: Kim
authors: Department of Pharmaceutical Science and Engineering, Seowon University, Cheongju, Korea.
authors: Bu Young
authors: BY
authors: Choi
authors: College of Pharmacy, Dongguk University, Goyang, Seowon University, Cheongju, Korea.
authors: Young-Sam
authors: YS
authors: Keum
keywords: (R)-2-hydroxyglutarate; 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one; Isocitrate; Isocitrate dehydrogenase-1; α-ketoglutarate