Design, synthesis and biological evaluation of novel thiazole-based derivatives as human Pin1 inhibitors

Pin1 is a peptidyl prolyl cis-trans isomerase (PPIase) and inhibiting Pin1 is a potential way for discovering antitumor agents. With an aim to find potent Pin1 inhibitors with a novel scaffold, a series of thiazole derivatives with an alicyclic heterocycles on the 2-position were designed, synthesized and tested against human Pin1. Compound 9p bearing a 2-oxa-6-azaspim [3,3] heptane moiety on the thiazole scaffold was identified as the most potent Pin1 inhibitor of this series with an IC50 value of 0.95 mu M. The structure-activity relationship (SAR) and molecular modeling study indicated that introducing an alicyclic ring with an H-bond acceptor would be a viable way to improve the binding affinity.

Automated summary

A series of thiazole derivatives with alicyclic heterocycles were designed, synthesized, and tested as potential Pin1 inhibitors. Compound 9p was identified as the most potent Pin1 inhibitor in the series, and introducing an alicyclic ring with an H-bond acceptor was found to improve binding affinity according to structure-activity relationship and molecular modeling studies.