How PROTACs Work: Why the ternary complex matters and it impacts degrader design
2023 Promega Sponsored Seminar in Targeted Protein Degradation
- Alessio Ciulli, PhD
- University of Dundee
Our laboratory uses molecular information on protein-protein interactions and protein degradation to discover novel therapeutics. Degrader molecules, also known as PROTACs (PROteolysis-Targeting Chimeras) recruit proteins to E3 ligases for targeted protein degradation. Formation of a ternary complex between the PROTAC, the E3 and the target leads to the tagging of the target protein by ubiquitination, and subsequent proteasomal degradation. In cancer, one such drug target is the E3 ubiquitin ligase VHL, which can be hijacked by PROTACs. Our lab solved crystal structures of VHL bound to fragments of its natural substrate and analysed it to design and synthesize novel small molecule ligands of VHL. We tethered the VHL ligand to a small molecule inhibitor targeting BRD4, a protein frequently deregulated in leukemia. The resulting PROTAC MZ1 bridges BRD4 with VHL and removes BRD4 from leukemic cells. Solving the structure of the ternary bridging complex, we unravelled how the PROTAC MZ1 induces selective degradation, illuminating structural and biophysical insights into PROTAC molecular recognition and mechanism of action. This fundamental understanding has enabled us to develop further small molecules for hard to target proteins and shown how to improve existing PROTACs.
Hosted by Drug DISCOVERY – Weiping Tang