@article{9c42fbcf4d6e4acba6fcec3838526d1b,
title = "Identification of a potent and selective covalent Pin1 inhibitor",
abstract = "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.",
author = "Pinch, \{Benika J.\} and Doctor, \{Zainab M.\} and Behnam Nabet and Browne, \{Christopher M.\} and Hyuk-Soo Seo and Mohardt, \{Mikaela L.\} and Shingo Kozono and Xiaolan Lian and Manz, \{Theresa D.\} and Yujin Chun and Shin Kibe and Daniel Zaidman and Dina Daitchman and Yeoh, \{Zoe C.\} and Vangos, \{Nicholas E.\} and Geffken, \{Ezekiel A.\} and Li Tan and Ficarro, \{Scott B.\} and Nir London and Marto, \{Jarrod A.\} and Stephen Buratowski and Sirano Dhe-Paganon and Zhou, \{Xiao Zhen\} and Lu, \{Kun Ping\} and Gray, \{Nathanael S.\}",
note = "We thank all members of the Gray laboratory for helpful discussions, M. Kostic for providing feedback on the manuscript and K. Westover for discussion of kinact and Ki calculations. This work was supported by the Ruth L. Kirschstein NRSA Individual Predoctoral Fellowship (grant no. F31 CA225066, B.J.P.), the Training Grant in Pharmacological Sciences (NIH grant no. T32 GM007306, B.J.P./Z.M.D), the Training Grant in Chemical Biology (NIH grant no. 5 T32 GM095450-04, B.J.P.), the Chleck Foundation (B.J.P./Z.M.D.), the American Cancer Society Postdoctoral Fellowship (grant no. PF-17-010-01-CDD, B.N.), the Claudia Adams Barr Program in Innovative Basic Cancer Research Award (B.N.), the Katherine L. and Steven C. Pinard Research Fund (N.S.G./B.N.), the Israel Science Foundation (grant no. 2462/19, N.L.), the Rising Tide Foundation (N.L.), the Israel Cancer Research Fund (N.L.), the Israeli Ministry of Science and Technology (grant no. 3-14763, N.L.), the Moross Integrated Cancer Center (N.L.), the Helen and Martin Kimmel Center for Molecular Design (N.L.), the Joel and Mady Dukler Fund for Cancer Research (N.L.), the Estate of Emile Mimran, Virgin JustGiving, the George Schwartzman Fund (N.L.), the National Institutes of Health R01s (grant no. R01 GM056663, S.B.), (grant no. R01 CA219850, grant no. R01 CA233800, J.A.M.), (grant no. R01 CA205153, N.S.G., K.P.L. and X.Z.Z.) and the Hale Center for Pancreatic Research (N.S.G.). BJP-02-118-2 and BJP-07-017-3 cocrystal structures were determined thanks to research conducted at the Advanced Photon Source on the Northeastern Collaborative Access Team beamlines (grant no. NIGMS P41 GM103403). Contributions - B.J.P. performed the chemical synthesis and biological characterization and wrote the manuscript. Z.M.D. generated cell lines and performed the GFP dropout experiment and RNA-sequencing analysis. B.N. generated cell lines and designed and supervised biological studies. C.M.B., S.B.F. and J.A.M. performed CITe-Id and mass spectrometry studies. M.L.M. assisted in Pin1 mutant cellular studies. S. Kozono, S. Kibe and X.L. performed the FP assay. D.Z., D.D. and N.L. provided computational docking support. L.T. advised on compound design and T.D.M. provided support for the chemical synthesis and biological characterization. Z.C.Y., N.E.V., E.A.G. and H.-S.S. performed the protein expression and crystallography; H.-S.S. and S.D.-P. analyzed the crystallography data. Y.C. and S.B. performed the yeast complementation experiments and analysis. K.P.L. and X.Z.Z. helped supervise the project and provided experimental support. N.S.G. conceived of and led this study.",
year = "2020",
month = jun,
day = "1",
doi = "10.1038/s41589-020-0550-9",
language = "English",
volume = "16",
pages = "979--987",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Research",
number = "9",
}