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Identification of a potent and selective covalent Pin1 inhibitor

Nature Chemical Biology volume 16, pages 979–987 (2020)Cite this article

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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.

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Fig. 1: Structure-guided modification of d-PEPTIDE to yield optimized Pin1 binders.
Fig. 2: Biochemical and structural characterization of BJP-06-005-3.
Fig. 3: BJP-06-005-3 is selective and engages cellular Pin1.
Fig. 4: Pin1 cooperates with KRASG12V to promote cell transformation, and Pin1 loss leads to viability defects.
Fig. 5: BJP-06-005-3 impacts PDAC cell viability in a Pin1-mediated manner.
Fig. 6: BJP-06-005-3 affects expression of downstream Pin1 substrates, and cooperates with KRASG12V degradation.

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Data availability

CITe-Id data for BJP-06-005-3 are provided as an excel file, Supplementary Dataset 1. RNA-sequencing data have been deposited to NCBI GEO (accession GSE147340), and the analyzed data file is provided as an excel file, Supplementary Dataset 2. All structural data have been deposited in the PDB (PDB codes 6O33 and 6O34).

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Acknowledgements

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).

Author information

Author notes

  1. Christopher M. Browne

    Present address: Discovery Biology, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Boston, MA, USA

  2. These authors contributed equally: Zainab M. Doctor, Behnam Nabet.

Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Benika J. Pinch

  2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Benika J. Pinch, Zainab M. Doctor, Behnam Nabet, Christopher M. Browne, Hyuk-Soo Seo, Mikaela L. Mohardt, Theresa D. Manz, Zoe C. Yeoh, Nicholas E. Vangos, Ezekiel A. Geffken, Li Tan, Scott B. Ficarro, Sirano Dhe-Paganon & Nathanael S. Gray

  3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Benika J. Pinch, Zainab M. Doctor, Behnam Nabet, Christopher M. Browne, Hyuk-Soo Seo, Theresa D. Manz, Yujin Chun, Zoe C. Yeoh, Nicholas E. Vangos, Ezekiel A. Geffken, Stephen Buratowski, Sirano Dhe-Paganon & Nathanael S. Gray

  4. Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Shingo Kozono, Xiaolan Lian, Shin Kibe, Xiao Zhen Zhou & Kun Ping Lu

  5. Department of Pharmacological and Medicinal Chemistry, Saarland University, Saarbruecken, Germany

    Theresa D. Manz

  6. Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel

    Daniel Zaidman, Dina Daitchman & Nir London

  7. Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA

    Scott B. Ficarro & Jarrod A. Marto

  8. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Jarrod A. Marto

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  1. Benika J. Pinch
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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.

Corresponding authors

Correspondence to Kun Ping Lu or Nathanael S. Gray.

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Competing interests

N.S.G. is a Scientific Founder and member of the Scientific Advisory Board (SAB) of C4 Therapeutics, Syros, Soltego, Gatekeeper and Petra Pharmaceuticals, and has received research funding from Novartis, Astellas, Taiho and Deerfield. J.A.M. serves on the SAB of 908 Devices, Boston, MA, and receives sponsored research support from Vertex and AstraZeneca. N.L. is a member of the SAB of Trilogy Sciences and has received research support from Teva. B.J.P., N.S.G., H.-S.S., S.D.-P., Z.M.D., C.M.B., J.A.M., S. Kozono, X.L., K.P.L. and X.Z.Z. are inventors on a patent application related to the Pin1 inhibitors described in this manuscript (WO/2019/241496). B.N. is an inventor on patent applications related to the dTAG system described in this manuscript (WO/2017/024318, WO/2017/024319, WO/2018/148443, WO/2018/148440). K.P.L. and X.Z.Z. are inventors on many issued patents or pending patent applications related to Pin1 inhibitors and/or biomarkers.

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Supplementary information

Supplementary Information (download PDF )

Supplementary Tables 1–4, Figs. 1–18 and Note

Reporting Summary (download PDF )

Supplementary Dataset 1 (download XLSX )

Raw CITe-Id data for BJP-06-005-3.

Supplementary Dataset 2 (download XLSX )

Analyzed RNAseq data for BJP-06-005-3, normalized relative to DMSO and BJP-R.

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Pinch, B.J., Doctor, Z.M., Nabet, B. et al. Identification of a potent and selective covalent Pin1 inhibitor. Nat Chem Biol 16, 979–987 (2020). https://doi.org/10.1038/s41589-020-0550-9

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