Webinar Overview:
This webinar is intended for those interested in learning about how the ubiquitin-proteasome system (UPS) can be exploited for inducing targeted protein degradation, and for those who are working on developing proteolysis-targeting chimeric molecules (PROTACs) and other molecular degraders. The webinar will discuss mechanistic biochemistry and pharmacology of the UPS and the E3 ligases involved; will highlight some of the assays and technologies available to study the pathways and interactions; and offer insights on how to design and optimize degrader molecules. Details to be discussed in the talks are given below.

Insights into Protein Degradation and Pharmacodynamic Predictions
Stewart Fisher, PhD, Chief Scientific Officer, C4 Therapeutics
Targeted protein degradation, a transformative new drug discovery approach, utilizes small molecule degraders to leverage the cellular protein recycling machinery to induce target protein destruction. Specifically, these degraders act as catalytic activators for an E3 ligase to initiate target protein ubiquitination, and the subsequent ubiquitinated target protein is recognized by the cellular proteasome for degradation. This talk will discuss the application of an enzymology framework to characterize cellular degradation data and the extension of these insights to pharmacodynamic modeling and predictions.

Targeted Protein Degradation: How PROTACs Work and Why the Ternary Complex Matters
Alessio Ciulli, PhD, Professor of Chemical and Structural Biology, School of Life Sciences, University of Dundee
Bifunctional degrader molecules (also known as PROTACs) recruit proteins to E3 ubiquitin ligases for targeted protein degradation. Formation of a ternary complex between the PROTAC, the ligase and the target, leads to the tagging of the target protein by ubiquitination, and subsequent proteasomal degradation. In recent years my lab has illuminated fundamental structural and biophysical understanding of PROTAC molecular recognition and mechanism of action, including solving the first crystal structure of a PROTAC ternary complex. We have shown how a PROTAC can “glue” the ligase and the target protein together, by forming proximity-induced neo protein-protein interactions that contribute to cooperativity and stability of ternary complexes. We have also shown that cooperative, stable, and kinetically long-lived ternary complexes drive faster and more profound protein degradation. These features of ternary complexes matter because they underpin the degradation potency, selectivity, and efficacy of PROTAC degraders, make them less dependent on binary binding affinities, and so usher targeting high-hanging fruit and traditionally hard-to-drug targets. These insights into the mode-of-action provide guiding principles to rationally design high-quality PROTAC degraders for translation chemical biology and drug discovery.

Learning Objectives:

• Overview of various types of protein degraders- PROTACs, molecular glues and more
• Understanding the PROTAC ternary complex and important insights into its mechanism of action
• Hearing about strategies for degrader optimization
• Learning about the quantitative structure-activity relationships (SAR) elements required for lead degrader optimization
• Understanding the linkage of pharmacokinetic and pharmacodynamic (PKPD) effects and efficacy
• Discussing examples of applying structure based PROTAC design for challenging drug targets

Speakers:

Stewart Fisher, PhD
Chief Scientific Officer
C4 Therapeutics

Dr. Fisher is the Chief Scientific Officer at C4 Therapeutics, a new biotechnology company focused on the selective recruitment of targets to E3 ligases for ubiquitination and degradation by the ubiquitin/proteasome system where he is responsible for strategic delivery of the project portfolio and collaboration management. Prior to joining C4, Dr. Fisher was the Director of Enzymology and Quantitative Biochemistry in the Center for the Development of Therapeutics at the Broad Institute. His group focused on the mechanistic analysis and quantitative assessment of protein-ligand interactions required for therapeutic discovery. Prior to joining the Broad Institute, Dr. Fisher spent 15 years at AstraZeneca in the Infectious Diseases Innovative Medicines Unit, where he led numerous antibacterial programs that progressed through Phase I clinical trials and was the Executive Director, Biological Sciences. His department supported the entire drug discovery project portfolio, from target validation to pharmacodynamics modeling in support of Phase III candidates. In addition, Dr. Fisher spent 2 years at Hoffmann LaRoche leading drug discovery programs in Metabolic Diseases. Dr. Fisher received his B.A. in Chemistry at the University of Vermont and Ph.D. in Chemistry at Caltech and was a National Institutes of Health Post-Doctoral Fellow at the Harvard Medical School with Professor Christopher T. Walsh.

Alessio Ciulli, PhD
Professor of Chemical and Structural Biology, School of Life Sciences
University of Dundee

Alessio Ciulli holds the Personal Chair of Chemical and Structural Biology at the School of Life Sciences, University of Dundee. Research in his laboratory focuses on developing small molecules inducing protein degradation and targeting protein-protein interactions (PPIs). He is the scientific founder of Amphista Therapeutics, a company that develops new protein degradation platforms. Alessio’s group has made significant contributions to selective chemical intervention on important PPI targets and to the development of targeted protein degradation (PROTACs). These include the fragment-based design of drug-like ligands for the von Hippel-Lindau (VHL) E3 ligase; the discovery of a first VHL-based degrader molecule (MZ1); and solving unprecedented crystal structure of a PROTAC ternary complex. These discoveries jump-started the PROTAC field and led to significant commercial impact across academia and biopharma worldwide. Alessio graduated in Chemistry from his hometown Florence, Italy (2002) and obtained a PhD in Chemical Biology from Cambridge, UK (2006). Following post-doctoral research at Cambridge, and a short HFSP visiting Fellowship at Yale University, he returned to Cambridge in 2009 to start his independent career and research group. In 2013 Alessio moved to Dundee and was promoted to Full Professor in 2016. He is a Fellow of the Royal Society of Chemistry and recipient of several prestigious awards.