Isocitrate dehydrogenase (IDH) is an enzyme that catalyses the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (α-KG) relative to the hydroxylation of substrates. However, IDH mutants can further reduce α-KG to 2-hydroxyglutarate (2-HG) which competitively inhibits α-KG dependent enzymes, leading to the downregulation of normal hydroxylation pathways. Good IDH mutant inhibitors can effectively reduce the level of 2-HG and therefore disturb cellular malignant transformation. In this review, we introduce the biological functions of IDH, describe the tumorigenesis mechanisms of IDH variants, and review the structure-based drug discovery of clinical inhibitors during 2012-2024. We also find successful applications of covalent strategy in the development of irreversible IDH inhibitors. Biological screening methods are also collected in this paper, which may help researchers to rapidly construct workflows for drug discovery and development.
Keywords: Covalent inhibitors; IDH mutants; Structure-based drug discovery; Targeted molecular therapy.
Copyright © 2024. Published by Elsevier Masson SAS.