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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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