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<p>Cancer remains a paramount threat to global health and constitutes a critical frontier in contemporary drug discovery. The pyrazolo[3,4-<i>d</i>]pyrimidine scaffold represents a unique chemical architecture that merges purine and pyrimidine pharmacophores, enabling profound exploration and clinical translation across anti-cancer therapeutic domains. The development of dual-target inhibitors represented a compelling strategy. This combinatorial approach not only amplified pharmacological efficacy through synergistic pathway suppression but also reduced the likelihood of resistance development by disrupting redundant survival networks. This review focused on the emerging paradigm of pyrazolo[3,4-<i>d</i>]pyrimidine-based dual-target inhibitors in oncology. Specifically, we systematically analyzed seven distinct dual-inhibition paradigms: AK/CDK1, HDAC/Topo II, CDK2/GSK-3β, Src/Bcr-Abl, BRAF V600E/VEGFR2, EGFR/PDE5, and EGFR T790M/HER2. Comprehensive insights were provided into the rational design principles, the structure–activity relationships (SARs), and molecular mechanisms underlying these innovative therapeutics. Furthermore, we proposed forward-looking strategies for design, ADME profiling, and toxicity mitigation to guide the translational development of pyrazolo[3,4-<i>d</i>]pyrimidine derivatives in cancer therapy.</p>

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Recent advances in Pyrazolo[3,4-d]pyrimidine-based dual inhibitors in the treatment of cancers

  • 期刊论文

  • 发表日期：

    2025年10月16日

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  • Hanrui Jiang,
  • Nan Li,
  • Ruosong Qin,
  • Siyu Lin,
  • Xuelian Wang,
  • Chunyan Li,
  • Jiwei Shen,
  • Ye Chen,
  • Ju Liu,
  • Shi Ding

摘要

Cancer remains a paramount threat to global health and constitutes a critical frontier in contemporary drug discovery. The pyrazolo[3,4-d]pyrimidine scaffold represents a unique chemical architecture that merges purine and pyrimidine pharmacophores, enabling profound exploration and clinical translation across anti-cancer therapeutic domains. The development of dual-target inhibitors represented a compelling strategy. This combinatorial approach not only amplified pharmacological efficacy through synergistic pathway suppression but also reduced the likelihood of resistance development by disrupting redundant survival networks. This review focused on the emerging paradigm of pyrazolo[3,4-d]pyrimidine-based dual-target inhibitors in oncology. Specifically, we systematically analyzed seven distinct dual-inhibition paradigms: AK/CDK1, HDAC/Topo II, CDK2/GSK-3β, Src/Bcr-Abl, BRAF V600E/VEGFR2, EGFR/PDE5, and EGFR T790M/HER2. Comprehensive insights were provided into the rational design principles, the structure–activity relationships (SARs), and molecular mechanisms underlying these innovative therapeutics. Furthermore, we proposed forward-looking strategies for design, ADME profiling, and toxicity mitigation to guide the translational development of pyrazolo[3,4-d]pyrimidine derivatives in cancer therapy.