2. Academic Validation
  3. Discovery of the first ataxia telangiectasia and Rad3-related (ATR) degraders for cancer treatment

Discovery of the first ataxia telangiectasia and Rad3-related (ATR) degraders for cancer treatment

  • Eur J Med Chem. 2024 Mar 5:267:116159. doi: 10.1016/j.ejmech.2024.116159.
Lei Huang 1,  Jialu Shao 2,  Wenwen Lai 2,  Hongfeng Gu 2,  Jieping Yang 2,  Shi Shi 2,  Shepherd Wufoyrwoth 2,  Zhe Song 3,  Yi Zou 4,  Yungen Xu 5,  Qihua Zhu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Department of Pharmacology and Medicinal Chemistry, Jiangsu Vocational College of Medicine, Yancheng, 224005, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 China Pharmaceutical University Center for Analysis and Testing, China Pharmaceutical University, Nanjing, 211198, China.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: zouyi@cpu.edu.cn.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: xyg@cpu.edu.cn.
  • 6 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: zhuqihua@vip.126.com.
PMID: 38325007 DOI: 10.1016/j.ejmech.2024.116159
Abstract

The first examples of ataxia telangiectasia and Rad3-related (ATR) PROTACs were designed and synthesized. Among them, the most potent degrader, ZS-7, demonstrated selective and effective ATR degradation in ATM-deficient LoVo cells, with a DC50 value of 0.53 μM. Proteasome-mediated ATR degradation by ZS-7 lasted approximately 12 h after washout in the LoVo cell lines. Notably, ZS-7 demonstrated reasonable PK profiles and, as a single agent or in combination with cisplatin, showed improved antitumor activity and safety profiles compared with the parent inhibitor AZD6738 in a xenograft mouse model of LoVo human colorectal Cancer cells upon intraperitoneal (i.p.) administration.

Keywords

ATR; Antitumor activity; Degradation; PROTAC; Proteasome; Xenograft model.

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