How Metabolism Informs Cancer Drug Discovery

Abstract

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to α‐ketoglutarate (αKG) in the cytoplasm/peroxisomes and mitochondria, respectively. Mutations in either IDH1 or IDH2 were identified in more than 70% of grade II–III gliomas as well as secondary glioblastomas, approximately 20% of patients with acute myeloid leukemia, and more recently in a significant proportion of cartilaginous tumors. We have previously demonstrated that IDH1R132, IDH2R140 and IDH2R172 mutant enzymes display decreased ability to catalyze the oxidation of isocitrate and acquire the ability to catalyze the reduction of αKG to the D‐2‐hydroxyglutrate (D‐2HG). The metabolic convergence of mutant IDH enzymes towards the production of 2HG supports the notion that this metabolite is linked to malignancy. Recent studies have shown that 2HG interferes with the activity of members of the superfamily of αKG‐dependent dioxygenases that catalyze a wide range of biochemical reactions whose deregulation has been associated with malignancy. Thus, the metabolic product of mutant IDH1 and IDH2 enzymes could impact an array of cancer relevant processes, including epigenetics and gene transcription. Based on the genetics and emerging prognostic correlations, mutant IDH1 and IDH2 have emerged as potential therapeutic targets. To that end, we have made significant progress in the identification of selective small molecule inhibitors and in understanding the biology of IDH mutations and D‐2HG. The therapeutic potential of targeting mutant IDH enzymes is currently being evaluated.