Identification of a potent and selective covalent Pin1 inhibitor.

Publication Type:

Journal Article


Nat Chem Biol, Volume 16, Issue 9, p.979-987 (2020)


Animals, Antineoplastic Agents, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Survival, Cell Transformation, Neoplastic, Crystallography, X-Ray, Cysteine, Drug Design, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Mice, NIH 3T3 Cells, NIMA-Interacting Peptidylprolyl Isomerase, Pancreatic Neoplasms, Protein Conformation, Proto-Oncogene Proteins p21(ras)


<p>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.</p>

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