Identification and structure-activity relationship optimization of dibromoacetophenones as novel mIDH1 inhibitors

Mutations at arginine 132 in isocitrate dehydrogenase 1 (IDH1) are prevalent in various cancers, making them attractive therapeutic targets. Here, we report the discovery and optimization of a novel dual inhibitor. Initial screening of an in-house library identified lead compound 1-1, which inhibited IDH1 R132H by 73.6 % at 2 μM. Iterative SAR efforts yielded compound 27j with subnanomolar potency against IDH1 R132H and R132C (IC₅₀ = 80.0 and 58.0 nM) and minimal activity against wt-IDH1/2. Notably, 27j also inhibits PDK1 (IC₅₀ = 0.61 μM), reducing PDH phosphorylation dose-dependently. It significantly suppressed 2-HG production in U87-MG IDH1 R132H and HT1080 cells (EC₅₀ = 69.0 and 121.1 nM). In phenotypic assays, 27j inhibited U87-MG IDH1 R132H cell proliferation (GC₅₀ = 1.4 μM), induced S-phase arrest, and promoted Apoptosis, with limited toxicity to normal L02 cells. These results highlight 27j as a potent mIDH1/PDK1 dual inhibitor for further development.