Discovery and Characterization of a Potent and Selective Pin1 Inhibitor Targeted to an Active Cysteine Site

We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity, and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer, with the negative control compound BJP-06-115-3 (BJP-R). RNA-sequencing was performed to characterize the transcriptome-wide effects of 4h compound treatment. Profiling of the effects of the covalent Pin1 inhibitor BJP-06-005-3 and the negative control BJP-06-115-3 (BJP-R) with the control DMSO for 4h in PATU-8988T cells.