Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy
Xin Han, Yi Sun
Abstract
In the past two decades, we have witnessed the discovery and development of many potent and efficacious proteolysis-targeting chimera (PROTAC) degraders, with several in phase I/II clinical trials. However, achieving good oral bioavailability for these degraders remains one of the biggest challenges, given the fact that PROTACs are often “beyond rule of 5” for small-molecule drugs because of their higher molecular weight and other poor physiochemical properties. In this review, we focus on the current efforts in the discovery and development of various orally available anti-cancer PROTAC degraders, and comprehensively summarize the strategies applied to this end. We believe that the strategies summarized here may provide a reference for future discovery of new oral-available PROTAC degraders for the treatment of various human diseases.