2. Academic Validation
  3. Rational Design of Novel pyrazolo[4,3- c]quinoline Derivatives as Potent, Selective, and Orally Bioavailable ATM Inhibitors with Promising In Vivo Efficacy

Rational Design of Novel pyrazolo[4,3- c]quinoline Derivatives as Potent, Selective, and Orally Bioavailable ATM Inhibitors with Promising In Vivo Efficacy

  • J Med Chem. 2026 Feb 26;69(4):4677-4696. doi: 10.1021/acs.jmedchem.5c03290.
Tao Yang 1 2,  Tao Guo 3,  Yongting Yuan 3,  Minghai Tang 3,  Xue Cui 3,  Min Zhao 4,  Meng Qin 1,  Zhuang Yang 3
Affiliations

Affiliations

  • 1 National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China.
  • 3 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 41669834 DOI: 10.1021/acs.jmedchem.5c03290
Abstract

ATM plays a pivotal role in the repair of DNA double-strand breaks, and its inhibition has been shown to sensitize colorectal Cancer cells to both chemotherapy and radiotherapy, highlighting its potential as a therapeutic target in colorectal Cancer. In this study, rational structural design led to the development of a series of pyrazolo[4,3-c]quinoline derivatives, with good ATM inhibitory activity and enhanced inhibition of DNA-PK. Through systematic structural optimization aimed at improving ATM selectivity and in vitro metabolic stability, the optimized compound A36 was identified. A36 demonstrated potent subnanomolar ATM inhibition, excellent kinase selectivity, strong cellular sensitization to radiation and chemotherapeutic agents, and favorable pharmacokinetic properties (F% = 80.5%). Moreover, in combination with irinotecan, A36 exhibited enhanced antitumor efficacy and synergistic effects in the HCT116 and SW620 colorectal Cancer xenograft models, with a best TGI of 92.6 and 91.1%, respectively, positioning it as a promising candidate for combination chemotherapy in colorectal Cancer treatment.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-181786
    ATM Kinase抑制剂
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