Abstract

Target class approaches to inhibitor discovery, whereby focused chemical libraries and a robust assay platform that prospectively measures selectivity are employed to find hits and leads for many members of a gene family, have enabled rapid development of inhibitors for kinases, GPCRs, bromodomains and other target classes. DUBs are an attractive class for this approach based on having central roles in biology, well-studied and unexplored members, available structural data, and established in vitro assay platforms. However, a lack of bona fide potent and selective DUB ligands or privileged scaffolds has hindered effective implementation of this strategy. To tackle this limitation, we have taken a multi-pronged approach to discovery and generation of hits and lead for individual DUBs and DUB-focused libraries. Our strategies have included comprehensive characterization of reported DUB inhibitors, screening of 50K diversity set against 8 DUBs, and design, synthesis and characterization of a DUB-targeted covalent library. I will describe our established DUB discovery platform and present vignettes of lessons learned and projects that have emerged from our chemistry-centric approach to studying DUBs.