WORKSHOP A - Tuesday, March 16 2021
Exploring the Autophagy-Lysosomal Pathway to Discover Novel Targeted Protein Degradation Strategies
10:30 – 12:30
The autophagy-lysosome pathway is becoming increasingly appreciated as playing a role in diverse diseases, including forms of neurodegeneration, infectious and inflammatory diseases and cancers. A growing literature suggests that strategies that may induce or inhibit autophagic flux can ameliorate such diseases, depending on their biology, based on cell and animal models. The next phases involve testing such strategies in human diseases. Such approaches may involve inhibiting the pathway at different points (for example in some cancers), or inducing bulk autophagy or pathways that enable some selective clearance of particular substrates. This workshop will consider target selection, target validation and strategies for therapeutic development.
Join this session to:
• How to identify suitable targets for autophagy modulation?
• How to validate autophagy targets in specific diseases?
• What approaches may be suitable for screening for autophagy modulators?
• What is the potential for designing strategies for selective autophagic clearance of toxic proteins?
• While much of the discussion will be around macroautophagy, it is important to consider the potential of other pathways, particularly chaperone-mediated autophagy
Professor of Molecular Neurogenetics & UK Dementia Research Institute
University of Cambridge
WORKSHOP B - Tuesday, March 16 2021
Mathematical Understanding of the Target Engagement or Ternary Complex Formation by the PROTAC or Molecular Glue Compounds and its Practical Implications
13:30 – 16:00
The target engagement for these molecules is a ternary complex (TC) formation among the target protein, the small molecule, and an E3 ubiquitin ligase protein. Unlike the traditional drugs where the target engagement can be described by a simple bimolecular equilibrium equation, there is currently no mathematical tools that can properly describe such complex multi-body interactions, which substantially increases the challenge in developing drugs of this mechanism. Due to the complex nature of the system,
various conflicting empirical theories have been put forward in the past regarding optimal properties of these molecules.
This workshop will provide multiple mathematical tools to address kinetics and equilibrium binding properties of the ternary complex formation, and practical implications will be discussed based on theoretical understanding of the system.
Join this session to:
• What are the practical implications of the “hook effect”? Why do I not observe the hook effect in my system? What does it tell us when that happens?
• What are the equivalent concepts in PROTAC world for Kd, EC50, Bmax, effective concentrations, etc., and how to deduce them from biochemical measurements?
• Given the same cellular system, what determines efficacy of different PROTAC molecules? How to choose one PROTAC over others from in vitro ternary complex assays? In other words, what parameters to use for SAR?
• Why do my PROTAC molecules fail to degrade the target protein? When different in vitro assays provide different pictures, how do I know which one to believe? How do I know when to quit or what aspect of the molecule needs to be improved?
• How to design PROTAC molecules to maximize efficacy and minimize toxicity? Is there such a thing as optimal affinity? Is extreme high affinity bad? What about covalent PROTAC?
• How to overcome low exposure? How to minimize effect of hook effect or decreased efficacy at high dose?
• How to design tox studies given the complex nature of the system? Should tox study design any different from traditional drugs?