Recent advances in dual PROTACs degrader strategies for disease treatment.

ABSTRACT

Proteolysis-targeting chimeras (PROTACs) is regarded as an emerging therapeutic strategy with unlimited potential because of its mechanism of inducing target protein degradation though harnessing ubiquitin-proteasome system (UPS). Recently, researchers are combining the advantages of PROTACs and dual-targeted drugs to explore some new types of dual PROTACs degraders. The utilization of dual PROTACs not only enhances the efficiency of selective degradation for two or more distinct proteins, but also facilitates synergistic interactions between target proteins to optimize therapeutic efficacy as well as overcome resistance. In this review, we briefly investigate the innovative strategies of dual degraders based on bivalent or trivalent "Y-type" PROTACs in recent years, outline their design principles, degradation effects, and anticancer activities. Moreover, their advantages and limitations compared with traditional PROTACs will be discussed and provide the outlook on the associated challenges. Meaningfully, the development and application of these dual-targeted PROTACs may point out new directions for replacing numerous combination regimens in the future.