The Future of Heterobifunctional Compounds: PROTACs and Beyond

Successful development of targeted protein degraders relies on good characterization and understanding of the mechanism of action and the drug properties that govern the pharmacology of degraders. This chapter explores the properties related to drug metabolism, pharmacokinetics, and pharmacodynamics (DMPK-PD) of degraders. It is intended to give a broad outline of the fundamental concepts relating to the physicochemical properties and their impact on the absorption, distribution, metabolism, and excretion (ADME) profiles of degraders, as well as to provide an overview of the available tools to characterize and quantify these properties. Additionally, the importance of good experimental design and the role of computational models in characterizing and predicting the PK/PD profiles of degraders, both in early development and in the clinics, is discussed. Gathering this information and insights is crucial to allow the selection of a degrader dose that is both safe and efficacious to the patient.