Targeted protein degradation in oncology: novel therapeutic opportunity for solid tumours?

Abstract

Targeted and immune therapies have improved patient outcomes in selected diseases. Still, resistance inevitably occurs, and a significant portion of the proteome remains undruggable due to target localisation, structural or functional constraints. Targeted protein degraders (TPDs) represent a promising strategy to expand druggable targets by redirecting the ubiquitin–proteasome system to selectively degrade proteins of interest (POI). TPDs include proteolysis-targeting chimeras (PROTACs), which are heterobifunctional molecules that create a ternary complex with the POI and the E3 ligase, and molecular glues (MGs), which are monovalent small molecules that create an interface between an E3 ligase and the POI. Here, we provide a viewpoint on novel therapeutic opportunities offered by TPDs, notably through the targeting of previously undruggable proteins or overcoming some resistance mechanisms. We further present challenges that will need to be addressed in order to optimise clinical development, including dose optimisation, patient selection and drug delivery.