Recent Progress in DNA Damage Response-Targeting PROTAC Degraders

Abstract

DNA damage response (DDR) defects in cells play a crucial role in tumor development by promoting DNA mutations. These mutations create vulnerabilities specific to cancer cells, which can be effectively targeted through synthetic lethality-based therapies. To date, numerous small molecule DDR inhibitors have been identified, and some of them have already been approved for clinical use. However, due to the complexity of the tumor microenvironment, mutations may occur in the amino acid residues of DDR targets. These mutations can affect the efficacy of small molecule inhibitors targeting DDR pathways. Therefore, researchers have turned their attention to next-generation DNA damage repair modulators, particularly those based on PROTAC technology. From this perspective, we overviewed the recent progress on DDR-targeting PROTAC degraders for cancer therapy. In addition, we also summarized the biological functions of different DDR targets. Finally, the challenges and future directions for DDR-target PROTAC degraders are also discussed in detail. ■ SIGNIFICANCECurrently, PROTAC degraders have been widely applied in the field of DDR-targeted drug discovery. This Perspective aims to provide a comprehensive overview of the current status and future perspectives in DDR-targeting PROTAC degraders for cancer therapy. Furthermore, it offers valuable insights into the rational design strategies and hurdles encountered during the development of DDR-targeting PROTAC degraders.