Some have been intractable because their active sites are broad, shallow pockets that are difficult to bridge with small molecules others have ‘smooth’ surfaces that offer few sites for a small molecule to bind. Targeted protein degradation (TPD) is attracting substantial interest owing to its potential to therapeutically modulate proteins that have proved difficult to target with conventional small molecules. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. ![]() ![]() Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules.
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