2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase for the Efficient Treatment of Cancer

Design, Synthesis, and Biological Evaluation of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase for the Efficient Treatment of Cancer

  • Molecules. 2023 Jun 2;28(11):4521. doi: 10.3390/molecules28114521.
Jialu Shao 1,  Lei Huang 1 2,  Wenwen Lai 1,  Yi Zou 1,  Qihua Zhu 1 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Pharmacology and Medicinal Chemistry, Jiangsu Vocational College of Medicine, Yancheng 224005, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
PMID: 37298997 DOI: 10.3390/molecules28114521
Abstract

Ataxia telangiectasia mutated and Rad3-related (ATR), a vital member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, plays a critical role in the DNA damage response (DDR). Tumor cells with a loss of DDR function or defects in the ataxia telangiectasia mutated (ATM) gene are generally more dependent on ATR for survival, suggesting that ATR is an attractive Anticancer drug target based on its synthetic lethality. Herein, we present a potent and highly selective ATR Inhibitor, ZH-12 (IC50 = 0.0068 μM). It showed potent antitumor activity as a single agent or in combination with cisplatin in the human colorectal adenocarcinoma LoVo tumor xenograft mouse model. Overall, ZH-12 may be a promising ATR Inhibitor based on the principle of synthetic lethality and deserves further in-depth study.

Keywords

ATM; ATR; ATR inhibitors; DDR; cancer; synthetic lethality.

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