Recent advances of IDH1 mutant inhibitor in cancer therapy

Isocitrate dehydrogenase (IDH) is the key metabolic enzyme that catalyzes the conversion of isocitrate to alpha-ketoglutarate (alpha-KG). Two main types of IDH1 and IDH2 are present in humans. In recent years, mutations in IDH have been observed in several tumors, including glioma, acute myeloid leukemia, and chondrosarcoma. Among them, the frequency of IDH1 mutations is higher than IDH2. IDH1 mutations have been shown to increase the conversion of alpha-KG to 2-hydroxyglutarate (2-HG). IDH1 mutation-mediated accumulation of 2-HG leads to epigenetic dysregulation, altering gene expression, and impairing cell differentiation. A rapidly emerging therapeutic approach is through the development of small molecule inhibitors targeting mutant IDH1 (mIDH1), as evidenced by the recently approved of the first selective IDH1 mutant inhibitor AG-120 (ivosidenib) for the treatment of IDH1-mutated AML. This review will focus on mIDH1 as a therapeutic target and provide an update on IDH1 mutant inhibitors in development and clinical trials.

Automated summary

IDH is a key metabolic enzyme that is mutated in various tumors, with IDH1 mutations being more frequent than IDH2 mutations. IDH1 mutations lead to accumulation of 2-HG, which impairs cell differentiation. Small molecule inhibitors targeting mutant IDH1 have emerged as a promising therapeutic approach.