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
  • 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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