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

Christian Dubiella, Benika J Pinch, Kazuhiro Koikawa, Daniel Zaidman, Evon Poon, Theresa D Manz, Behnam Nabet, Shuning He, Efrat Resnick, Adi Rogel, Ellen M Langer, Colin J Daniel, Hyuk-Soo Seo, Ying Chen, Guillaume Adelmant, Shabnam Sharifzadeh, Scott B Ficarro, Barbara Martins da Costa, Yann Jamin, Mark W ZimmermanXiaolan Lian, Shin Kibe, Shingo Kozono, Zainab M Doctor, Christopher M Browne, Annan Yang, Liat Stoler-Barak, Richa B Shah, Nicholas E Vangos, Ezekiel A Geffken, Roni Oren, Eriko Koide, Samuel Sidi, Ziv Shulman, Chu Wang, Jarrod A Marto, Sirano Dhe-Paganon, Thomas Look, Xiao Zhen Zhou, Kun Ping Lu, Rosalie C Sears, Louis Chesler, Nathanael S Gray*, Nir London*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)954-963
Number of pages10
JournalNature Chemical Biology
Volume17
Issue number9
DOIs
Publication statusPublished - Sept 2021

Funding

Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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