Current Progress in Isocitrate Dehydrogenase Mutations and Its Inhibitors in Gliomas / 中国药学杂志

Glioma is a primary brain tumor produced by canceration of the glial cells in the brain and spinal cord, accounting for 74.6% of the malignant tumors in the central nervous system. Isocitrate dehydrogenase (IDH) is the rate-limiting enzyme of the tricarboxylic acid cycle and catalyzes the oxidative decarboxylation of isocitrate to produce α-ketoglutarate (α-KG). Its mutant (mIDH) is a new point mutation, not only lose its original function but also gain new activity: catalyzing the production of carcinogenic R-2-hydroxyglutarate (2HG) by α-KG. Isocitrate dehydrogenase inhibitors can reduce the production of 2HG and induce the demethylation of histones, thereby inhibiting tumor progression. Although discovered in 2008, the mIDH has become a tumor diagnostic marker and therapeutic target, mIDH2 and mIDH1 inhibitors for acute myeloid leukemia have been approved for marketing in 2017and 2018,respectively.For the treatment of acute myeloid leukemia, the reliability of isocitrate dehydrogenase mutants as tumor therapeutic targets was confirmed.At present, many pharmaceutical institutions around the world are conducting research and development of isocitrate dehydrogenase inhibitors.This article reviews the current research status of current IDH inhibitors.

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

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.