Thursday, March 26, 2020

Sulfopin, a selective covalent inhibitor of Pin1, blocks Myc-driven tumor initiation and growth in vivo

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.

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,...