2. Academic Validation
  3. Design and Synthesis of Pyrrolo[3,4- d]pyrimidine-Based ATR Degraders for Effective Treatment of Colorectal Cancer in Mouse Model

Design and Synthesis of Pyrrolo[3,4- d]pyrimidine-Based ATR Degraders for Effective Treatment of Colorectal Cancer in Mouse Model

  • J Med Chem. 2026 Mar 26;69(6):6902-6928. doi: 10.1021/acs.jmedchem.5c03155.
Nian-Dong Mao 1 2 3,  Zi Hui 1,  Chen-Chen Wang 1 2 3,  Meng-Lan He 1 2,  Shun-Ran Li 1 2,  Meng-Qian Yu 1 2,  Lulu Ye 1 4,  Jia-Wei Zhou 1 2,  Zong-Hao Wang 1 2,  Bo-Qun Du 1 2,  Guo-Wei Ye 1 2,  Yu-Qing Zhang 1 2,  Xia Yao 1 2,  Xing-Lin Feng 4,  Frédéric Lirussi 5 6 7,  Carmen Garrido 5 8 9,  Yuan Gao 10,  Hui Luo 4,  Xiang-Yang Ye 1 2 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.
  • 2 Zhejiang Provincial Key Laboratory of Anti-Cancer Chinese Medicines and Natural Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.
  • 3 College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P. R. China.
  • 4 School of Clinical Medicine, Hangzhou Normal University, Hangzhou Zhejiang 311121, P. R. China.
  • 5 Centre for Translational and Molecular Medicine, INSERM UMR 1231, 21000 Dijon, France.
  • 6 Université de Franche-Comté, 25000 Besançon, France.
  • 7 Plateforme PACE, Laboratoire de Pharmacologie-Toxicologie, Centre Hospitalo-Universitaire, 25000 Besançon, France.
  • 8 Faculty of Medicine, University of Bourgogne, 21000 Dijon, France.
  • 9 Cancer Center Georges François Leclerc, 21000 Dijon, France.
  • 10 Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310000, China.
PMID: 41787651 DOI: 10.1021/acs.jmedchem.5c03155
Abstract

Ataxia telangiectasia and Rad3-related kinase (ATR) is a pivotal DNA damage response regulator. While several ATR inhibitors have entered clinical trials, none have yet been approved for therapeutic use. A potent ATR degrader A12 based on the pyrrolo[3,4-d]pyrimidine scaffold was designed and synthesized, with the ability not only to induce proteasomal degradation of ATR (DC50: 127 nM, Dmax: 72%) but also of Chk1 (DC50: 135 nM, Dmax: 70%) in several colorectal Cancer cells. It exhibits strong antiproliferative activity (IC50: 55 nM) and rapidly triggers Apoptosis. In LoVo xenograft mouse model, A12 monotherapy (30 mg/kg) achieved outstanding tumor growth inhibition (TGI: 74%) without apparent toxicity. Combination with A12 (10 mg/kg) and cetuximab (3 mg/kg) further enhanced efficacy (TGI: 81%) with a favorable safety profile. These findings highlight that ATR degraders such as A12, which also degrade Chk1 simultaneously, represents as a promising therapeutic strategy for colorectal Cancer and potentially Other tumor types.

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