Property-based optimisation of PROTACs

PROTACs are an emerging therapeutic approach towards targeted protein degradation. This article examines the leading examples of this modality that are in clinical development through the prism of their physicochemical properties. In particular, the optimisation of the various components of PROTACs together with the difficulties faced by medicinal chemists seeking to achieve oral bioavailability in this challenging space are outlined. Guidance, opinion and advice based on the authors' own experiences in this area are offered in the hope this may be useful to others working in this fascinating frontier of drug discovery.