Structure-Based Design of Novel Benzimidazole Derivatives as Pin1 Inhibitors.

Peptidyl-prolyl isomerase Pin1 plays a key role in amplifying and translating multiple oncogenic signaling pathways during oncogenesis. The blockade of Pin1 provided a unique way of disrupting multiple oncogenic pathways and inducing apoptosis. Aiming to develop potent Pin1 inhibitors, a series of benzimidazole derivatives were designed and synthesized. Among the derivatives, compounds and showed the most potent Pin1 inhibitory activity with IC values of 0.64 and 0.37 μM, respectively. In vitro antiproliferative assay demonstrated that compounds , , , , and exhibited moderate antiproliferative activity against human prostate cancer PC-3 cells. Taken together, these unique benzimidazole derivatives exhibited great potential to be further explored as potent Pin1 inhibitors with improved potency.