Identification of a potent and selective covalent Pin1 inhibitor

Benika J. Pinch, Zainab M. Doctor, Behnam Nabet, Christopher M. Browne, Hyuk-Soo Seo, Mikaela L. Mohardt, Shingo Kozono, Xiaolan Lian, Theresa D. Manz, Yujin Chun, Shin Kibe, Daniel Zaidman, Dina Daitchman, Zoe C. Yeoh, Nicholas E. Vangos, Ezekiel A. Geffken, Li Tan, Scott B. Ficarro, Nir London, Jarrod A. Marto, Stephen Buratowski, Sirano Dhe-Paganon, Xiao Zhen Zhou, Kun Ping Lu & Nathanael S. Gray

Nature Chemical Biology, 2020
DOI https://doi.org/10.1038/s41589-020-0550-9

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. 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. In parallel to inhibitor development, we employed genetic and chemical-genetic strategies to assess the consequences of Pin1 loss in human PDAC cell lines. We demonstrate that Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and that Pin1 inhibition impairs cell viability over time in PDAC cell lines.