Multiparameter Optimization of Oxidative Phosphorylation Inhibitors for the Treatment of Pancreatic Cancer

Targeting Oxidative Phosphorylation (OXPHOS) complexes is an emerging strategy to disrupt the metabolism of select Cancer subtypes and to overcome resistance to targeted therapies. Here, we describe our lead optimization campaign on a series of benzene-1,4-disulfonamides as novel OXPHOS complex I inhibitors. This effort led to the discovery of compound 23 (DX3-213B) as one of the most potent complex I inhibitors reported to date. DX3-213B disrupts adenosine triphosphate (ATP) generation, inhibits complex I function, and results in the growth inhibition of pancreatic Cancer cells in the low nanomolar range. Importantly, the oral administration of DX3-213B resulted in significant in vivo efficacy in a pancreatic Cancer syngeneic model without obvious toxicity. Our data clearly demonstrate that OXPHOS inhibition can be a safe and efficacious strategy to treat pancreatic Cancer.