@article{51555fa2c360436c93399f38d46122f9,
title = "Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo",
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{\textquoteright}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. [Figure not available: see fulltext.]",
author = "Christian Dubiella and Pinch, {Benika J.} and Kazuhiro Koikawa and Daniel Zaidman and Evon Poon and Manz, {Theresa D.} and Behnam Nabet and Shuning He and Efrat Resnick and Adi Rogel and Langer, {Ellen M.} and Daniel, {Colin J.} and Seo, {Hyuk Soo} and Ying Chen and Guillaume Adelmant and Shabnam Sharifzadeh and Ficarro, {Scott B.} and Yann Jamin and {Martins da Costa}, Barbara and Zimmerman, {Mark W.} and Xiaolan Lian and Shin Kibe and Shingo Kozono and Doctor, {Zainab M.} and Browne, {Christopher M.} and Annan Yang and Liat Stoler-Barak and Shah, {Richa B.} and Vangos, {Nicholas E.} and Geffken, {Ezekiel A.} and Roni Oren and Eriko Koide and Samuel Sidi and Ziv Shulman and Chu Wang and Marto, {Jarrod A.} and Sirano Dhe-Paganon and Thomas Look and Zhou, {Xiao Zhen} and Lu, {Kun Ping} and Sears, {Rosalie C.} and Louis Chesler and Gray, {Nathanael S.} and Nir London",
note = "Funding Information: N.S.G. is a Scientific Founder and member of the Scientific Advisory Board (SAB) of C4, Jengu, Inception, Larkspur, Syros, Soltego, Gatekeeper and Petra Pharmaceuticals and has received research funding from Novartis, Astellas, Taiho and Deerfield. N.L. is a member of the SAB of Totus medicines and Monte Rosa Therapeutics and has received research support from Teva and Pfizer. J.A.M. has received support through sponsored research agreements with AstraZeneca and Vertex. J.A.M. serves on the SAB of 908 Devices. C.M.B. is an employee of AstraZeneca. C.D., B.J.P., D.Z., S.H., X.L., K.P.L., X.Z.Z., T.L., N.S.G. and N.L. are inventors on a patent application related to the inhibitors described in this manuscript (no. PCT/IL2020/050043). Funding Information: N.L. is the incumbent of the Alan and Laraine Fischer Career Development Chair. N.L. thanks the Israel Science Foundation for funding (grant no. 2462/19), The Rising Tide Foundation, The Israel Cancer Research Fund, the Israeli Ministry of Science and Technology (grant no. 3-14763) and the Moross integrated cancer center. N.L. is also supported by the Helen and Martin Kimmel Center for Molecular Design, Joel and Mady Dukler Fund for Cancer Research, the Estate of Emile Mimran and Virgin JustGiving and the George Schwartzman Fund. C.D. was supported by the Minerva Fellowship program of the Max Planck Society, funded by the German Federal Ministry for Education and Research. This work was supported in part by NIH grant no. R01CA205153 to K.P.L., N.S.G. and X.Z.Z. N.S.G. was also supported by the Hale Center for Pancreatic Research. Y.C. and C.W. thank the Computing Platform of the Center for Life Science at Peking University for supporting proteomic data analysis. S.D.-P acknowledges funding from the Linde Family Foundation. Part of this research was conducted at the Advanced Photon Source on the Northeastern Collaborative Access Team beamlines (no. NIGMS P41 GM103403), and SBGrid compiled software (no. eLife 2013;2:e01456). J.A.M. acknowledges support from the National Institutes of Health (nos. CA233800 and TR002933) and the Mark Foundation for Cancer Research. B.J.P. was supported by the Ruth L. Kirschstein NRSA Individual Predoctoral Fellowship (no. F31 CA225066), the Training Grant in Pharmacological Sciences (no. NIH 5 T32 GM007306), the Training Grant in Chemical Biology (no. NIH 5 T32 GM095450-04) and the Chleck Foundation (also to Z.M.D.). B.N. was supported by an American Cancer Society Postdoctoral Fellowship (no. PF-17-010-01-CDD) and the Katherine L. and Steven C. Pinard Research Fund (also to N.S.G.). L.C. is supported by the Cancer Research UK Program Grant (nos. C34648/A18339 and C34648/A14610). Y.J. is supported by a Children with Cancer UK Research Fellowship (no. 2014/176). R.C.S. acknowledges funding support from NCI R01s (nos. CA196228 and CA186241) and foundation support from The Brenden-Colson Center for Pancreatic Care. We thank I. Ulitski for help with RNA-seq analysis, M. Kostic for critical reading of the manuscript, T.-M. Salame for help with FACS analysis and P. Gehrtz and I. You for helping with compound characterization. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = sep,
doi = "10.1038/s41589-021-00786-7",
language = "English (US)",
volume = "17",
pages = "954--963",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "9",
}