Targeting the DCN1-UBC12 Protein-Protein Interaction in the Neddylation Activation Complex
Recorded On: 02/07/2018
The Cullin-RING E3 ubiquitin ligases (CRLs) regulate homeostasis of approximately 20% of cellular proteins and their activation require neddylation of their cullin subunit. Cullin neddylation is modulated by a scaffolding DCN protein through interactions with both the cullin protein and an E2 enzyme such as UBC12. Here we report the discovery of high-affinity, cell-permeable small molecule inhibitors of the DCN1-UBC12 interaction. Using these small-molecule inhibitors as chemical probes, we have made a surprising discovery that the DCN1-UBC12 protein-protein interaction is much more important for the neddylation of cullin 3 over other cullin family members. Treatment of cells of different tissue types with these potent DCN1 inhibitors selectively convert cellular cullin 3 into a unneddylated inactive form with no or minimum effects on other cullin members. Our data firmly establish a previously unrecognized specific role of the DCN1-UBC12 interaction for cellular neddylation of cullin 3. Our compounds represent the first-in-class of selective inhibitors of a specific cullin member, and are excellent probe compounds to investigate the role of the cullin 3 ligase in biological processes and human diseases. We will also discuss their potential therapeutic applications.
University of Michigan
Dr. Wang received his B.S. in Chemistry from Peking University and his Ph.D. in Chemistry from Case Western Reserve University. Dr. Wang did his postdoctoral training in drug design at the National Cancer Institute, NIH between1992-1996. Wang is currently the Warner-Lambert/Parke-Davis Professor in Medicine i. Dr. Wang serves as the Co-Director of the Molecular Therapeutics Program at the University of Michigan Comprehensive Cancer Center and is the Director of the Cancer Drug Discovery Program at the University of Michigan. Dr. Wang is the Editor-in-Chief for Journal of Medicinal Chemistry, a premier international journal in medicinal chemistry and drug discovery by the American Chemical Society. Dr. Wang has published more than 270 papers in peer-reviewed scientific journals and 100+ meeting abstracts, and is an inventor on more than 48 patents and patent applications. In addition to his academic role, Dr Wang is a co-founder for several biotech companies.