Designing Targeted Protein Degraders

This lecture delves into the design, evaluation, and validation of targeted protein degraders (TPDs), focusing on hijacking the degradome for therapeutic interventions. It covers concepts like reversible vs. irreversible binders, events-driven pharmacology, and the ubiquitin proteasome system. The lecture explores the two foundational modalities in TPD, rationally designed degraders (PROTACs) and opportunistic degraders (molecular glue compounds), and discusses the minimum requirements for claiming TPD mode-of-action. Empirical validations of predicted models and the importance of proper analyses and validations in TPD research are also highlighted.