1. Academic Validation
  2. 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.
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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