Lessons learned in linking PROTACs from discovery to the clinic

Targeted protein degradation has the potential to deliver greater efficacy than conventional receptor antagonists or enzyme inhibitors and address previously undruggable targets. This has driven a recent surge of interest in protein degradation modalities. Bifunctional degraders, specifically proteolysis targeting chimeras (PROTACs), have become a key modality in the protein degrader space, despite the physicochemical challenges they present in achieving oral bioavailability. In this Review, we discuss the lessons learned to date in the optimization of PROTACs, with particular emphasis on the role of the linker region, including its role in optimization of pharmacology, impact on oral bioavailability, and influence on metabolic fate. The evolution from pharmacological tools to an established clinical modality, and the lessons that can be drawn from the preclinical data and the first cohort of PROTACs to reach the clinic, is discussed.