2. Academic Validation
  3. Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo

Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo

  • Nat Chem Biol. 2021 Sep;17(9):954-963. doi: 10.1038/s41589-021-00786-7.
Christian Dubiella  # 1,  Benika J Pinch  # 2 3 4,  Kazuhiro Koikawa 5 6 7,  Daniel Zaidman 1,  Evon Poon 8,  Theresa D Manz 2 3 9,  Behnam Nabet 2 3,  Shuning He 10,  Efrat Resnick 1,  Adi Rogel 1,  Ellen M Langer 11 12,  Colin J Daniel 11 12,  Hyuk-Soo Seo 2,  Ying Chen 13,  Guillaume Adelmant 2 14 15 16,  Shabnam Sharifzadeh 2 14 15 16,  Scott B Ficarro 2 14 15 16,  Yann Jamin 17,  Barbara Martins da Costa 8,  Mark W Zimmerman 10,  Xiaolan Lian 5 6 7,  Shin Kibe 5 6 7,  Shingo Kozono 5 6 7,  Zainab M Doctor 2 3,  Christopher M Browne 2 3 18,  Annan Yang 2 19,  Liat Stoler-Barak 20,  Richa B Shah 21 22,  Nicholas E Vangos 2,  Ezekiel A Geffken 2,  Roni Oren 23,  Eriko Koide 2 3,  Samuel Sidi 21 22,  Ziv Shulman 20,  Chu Wang 13,  Jarrod A Marto 2 14 15 16,  Sirano Dhe-Paganon 2,  Thomas Look 10 24,  Xiao Zhen Zhou 5 6 7,  Kun Ping Lu 5 6 7,  Rosalie C Sears 11 12 25,  Louis Chesler 8,  Nathanael S Gray 26 27 28,  Nir London 29
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Chemistry and Chemical Biology, Department of Chemical Biology, Harvard University, Cambridge, MA, USA.
  • 5 Department of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 6 Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 7 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 8 Division of Clinical Studies, The Institute of Cancer Research, London, UK.
  • 9 Department of Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbruecken, Germany.
  • 10 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 11 Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
  • 12 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 13 College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • 14 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 15 Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 16 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 17 Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
  • 18 Discovery Biology, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Boston, MA, USA.
  • 19 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 20 Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
  • 21 Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 22 Department of Cell, Developmental and Regenerative Biology, The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 23 Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel.
  • 24 Division of Pediatric Hematology/Oncology Boston Children's Hospital, Boston, MA, USA.
  • 25 Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR, USA.
  • 26 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. nsgray01@stanford.edu.
  • 27 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. nsgray01@stanford.edu.
  • 28 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA. nsgray01@stanford.edu.
  • 29 Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel. nir.london@weizmann.ac.il.
  • # Contributed equally.
PMID: 33972797 DOI: 10.1038/s41589-021-00786-7
Abstract

The peptidyl-prolyl isomerase, PIN1, is exploited in Cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, PIN1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar PIN1 Inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies PIN1 genetic knockout. PIN1 inhibition had only a modest effect on Cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic Cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that PIN1 warrants further investigation as a potential Cancer drug target.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-139361
    99.69%, Pin1 Inhibitor