Pharmacology of PROTAC Degrader Molecules

In this chapter, we discuss key considerations in the optimization of PROTACs for in vivo use. General concepts of PROTAC pharmacology are discussed and specific aspects, such as the potential for “hook effects” and the system dependence of degradation rate, are highlighted. Challenges in the optimization of pharmacokinetic properties, including difficulties in the application of typical in vitro screening cascades to PROTACs, the need for modification of physicochemical property limits and consideration of empirical pharmacokinetic data are discussed. The importance of the selection of protein of interest and E3 ligands and the opportunity to use the linker for modulation of overall physicochemical properties is illustrated by case studies of published PROTACs. The main PROTAC PKPD modelling approaches, based on ternary complex formation, are discussed and a “pragmatic” approach focusing on key properties that impact the PKPD of target degradation is also described. Key insights into the importance of endogenous target protein kinetics and target protein and ligase baseline levels will be covered. Understanding all these factors is highly recommended for any successful PROTAC discovery program.