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Rational Design of Novel pyrazolo[4,3-c]quinoline Derivatives as Potent, Selective, and Orally Bioavailable ATM

Tao Yang1,2, Tao Guo3, Yongting Yuan3

  • 1National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu 610041, China.

Journal of Medicinal Chemistry
|February 11, 2026
PubMed

Insights

A new compound, A36, effectively inhibits ATM kinase, enhancing colorectal cancer cell sensitivity to chemotherapy and radiation. This promising drug candidate shows significant tumor growth inhibition when combined with irinotecan.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • ATM is crucial for DNA double-strand break repair.
  • ATM inhibition sensitizes colorectal cancer cells to chemotherapy and radiotherapy.
  • ATM is a potential therapeutic target in colorectal cancer.

Purpose of the Study:

  • To develop novel pyrazolo[4,3-c]quinoline derivatives as ATM inhibitors.
  • To optimize compounds for ATM selectivity and metabolic stability.
  • To evaluate the efficacy of the optimized compound A36 in preclinical colorectal cancer models.

Main Methods:

  • Rational structural design and synthesis of pyrazolo[4,3-c]quinoline derivatives.
  • In vitro assays for ATM and DNA-PK inhibition.
  • In vitro metabolic stability and pharmacokinetic studies.
  • Colorectal cancer cell line studies for chemosensitization and radiosensitization.
  • In vivo efficacy studies using colorectal cancer xenograft models in combination with irinotecan.

Main Results:

  • A series of pyrazolo[4,3-c]quinoline derivatives with ATM inhibitory activity were developed.
  • The optimized compound A36 exhibited potent subnanomolar ATM inhibition and excellent kinase selectivity.
  • A36 demonstrated strong cellular sensitization to radiation and chemotherapeutic agents.
  • A36 showed favorable pharmacokinetic properties (F% = 80.5%).
  • Combination of A36 with irinotecan resulted in enhanced antitumor efficacy and synergistic effects in xenograft models (TGI up to 92.6%).

Conclusions:

  • Compound A36 is a potent and selective ATM inhibitor with favorable drug-like properties.
  • A36 effectively sensitizes colorectal cancer cells to standard therapies.
  • A36 shows significant promise as a therapeutic agent for combination chemotherapy in colorectal cancer treatment.

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