2. Academic Validation
  3. Recent Progress in DNA Damage Response-Targeting PROTAC Degraders

Recent Progress in DNA Damage Response-Targeting PROTAC Degraders

  • J Med Chem. 2024 May 9;67(9):6906-6921. doi: 10.1021/acs.jmedchem.4c00015.
Binbin Cheng 1,  Xiaoting Fei 1,  Zongbao Ding 2,  Xiaopeng Peng 3,  Zhenhong Su 1,  Wei Pan 4,  Jianjun Chen 5
Affiliations

Affiliations

  • 1 School of Medicine, Hubei Polytechnic University, Huangshi 435003, China.
  • 2 Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, China.
  • 3 College of Pharmacy, Gannan Medical University, Ganzhou, 314000, China.
  • 4 CardioIogy Department, Geriatric Department, Foshan Women and Children Hospital, Foshan, Guangdong 528000, China.
  • 5 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
PMID: 38663873 DOI: 10.1021/acs.jmedchem.4c00015
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.

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