2. Academic Validation
  3. Recent advances in DDR (DNA damage response) inhibitors for cancer therapy

Recent advances in DDR (DNA damage response) inhibitors for cancer therapy

  • Eur J Med Chem. 2022 Feb 15:230:114109. doi: 10.1016/j.ejmech.2022.114109.
Binbin Cheng 1,  Wei Pan 2,  Yi Xing 3,  Yao Xiao 4,  Jianjun Chen 5,  Zheng Xu 6
Affiliations

Affiliations

  • 1 School of Medicine, Hubei Polytechnic University, Huangshi, 435003, China.
  • 2 Department of Cardiology, The Sixth Affiliated Hospital, South China University of Technology, Nanhai People's Hospital, Foshan, Guangdong, 528200, China.
  • 3 Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
  • 4 Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan Wuchang Hospital, Wuchang, 430063, China.
  • 5 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China. Electronic address: jchen21@smu.edu.cn.
  • 6 College of Animal Science and National Engineering Center for Swine Breeding Industry, South China Agriculture University, Guangzhou, 510642, China. Electronic address: stonezen@scau.edu.cn.
PMID: 35051747 DOI: 10.1016/j.ejmech.2022.114109
Abstract

DDR (DNA damage response) defects in cells drive tumor formation by promoting DNA mutations, which also provides cancer-specific vulnerabilities that can be targeted by synthetic lethality-based therapies. Until now, PARP inhibitors like olaparib are the first successful case of utilizing synthetic lethality-based therapy to treat cancers with DNA-repairing deficiency (e.g. BRCA1 or BRCA2 mutation), which has fueled the search for more targetable components in the DDR signaling pathway by exploiting synthetic lethality, including but not limited to DNA-PK, ATR, ATM, Chk1, and Wee1. After years of efforts, numerous DDR kinase inhibitors have been discovered. Some of them are being investigated in clinical trials and have shown promising results for Cancer therapy. In this review, we summarize the latest advancement in the development of DDR kinase inhibitors including those in preclinical stages and clinical trials, the crystal structures of DDR Enzymes, and binding modes of inhibitors with target proteins. The biological functions involving different genes and proteins (ATR, DNA-PK, ATM, PARP, Chk1, and Wee1) are also elucidated.

Keywords

DNA damage Response; Small molecule inhibitors; Synthetic lethality.

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