Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity

Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1­(R132H). A total of 61 derivatives were synthesized, and their structure–activity relationships were investigated. Potent IDH1­(R132H) inhibitors were identified with K i values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1­(R132C) were found to be correlated with their inhibitory activities against IDH1­(R132H), as well as cellular production of D2HG, with R 2 of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood–brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26–1.8 μM) against glioma cells with the IDH1 R132H mutation.