Structure-guided design of α-amino acid-derived Pin1 inhibitors

The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of α-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC50 <100 nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10–50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.

Graphical abstractAn indole 2-carboxylic acid fragment was evolved into a series of potent (<200 nM) α-benzimidazolyl-substituted amino acid inhibitors of the Pin1 PPIase via structure-based drug design.Figure optionsDownload full-size imageDownload as PowerPoint slide