Christian Dubiella, Benika J. Pinch, Daniel Zaidman, Theresa D. Manz, Evon Poon, Shuning He, Efrat Resnick, Ellen M. Langer, Colin J. Daniel, Hyuk-Soo Seo, Ying Chen, Scott B. Ficarro, Yann Jamin, Xiaolan Lian, Shin Kibe, Shingo Kozono, Kazuhiro Koikawa, Zainab M. Doctor, Behnam Nabet, Christopher M. Browne, Annan Yang, Liat Stoler-Barak, Richa B. Shah, Nick E. Vangos, Ezekiel A. Geffken, Roni Oren, 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
BioRXiv, 2020
doi: https://doi.org/10.1101/2020.03.20.998443
The peptidyl-prolyl cis-trans isomerase, Pin1, acts as a unified signaling hub that is exploited in cancer to activate oncogenes and inactivate tumor suppressors, in particular through up-regulation of c-Myc target genes. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to discover covalent inhibitors targeting Pin1’s active site nucleophile - Cys113, leading to the development of Sulfopin, a double-digit nanomolar Pin1 inhibitor. Sulfopin is highly selective for Pin1, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement, and phenocopies genetic knockout of Pin1. Although Pin1 inhibition had a modest effect on viability in cancer cell cultures, Sulfopin induced downregulation of c-Myc target genes and reduced tumor initiation and tumor progression in murine and zebrafish models of MYCN-driven neuroblastoma. Our results suggest that Sulfopin is a suitable chemical probe for assessing Pin1-dependent pharmacology in cells and in vivo. Moreover, these studies indicate that Pin1 should be further investigated as a potential cancer target.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs.
Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1
Adrian Hall, Jan Abendroth, Madison J. Bolejack, Tom Ceska, Sylvie Dell’Aiera, Victoria Ellis, David Fox, Cyril François, Muigai M. Muruthi,...
-
Katharine Gilbert, Aini Vuorinen, Arron Aatkar Peter Pogány, Jonathan Pettinger, Joanna M. Kirkpatrick, Katrin Rittinger∥, David House, Glen...
-
Yejin Jung, Naotaka Noda, Junichiro Takaya, Masahiro Abo, Kohei Toh, Ken Tajiri, Changyi Cui, Lu Zhou, Shin-ichi Sato, and Motonari Uesugi A...
-
Meng Zhang, Angelo Aguilar, Shilin Xu, Liyue Huang, Krishnapriya Chinnaswamy, Taryn Sleger, Bo Wang, Stefan Gross, Brandon N. Nicolay, Sebas...