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<p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. The malignancy of HCC is closely linked to liver cancer stem cells (CSCs), making the application of anti-CSC drugs a promising therapeutic approach. In this study, we report the discovery of novel pyrrolo[2,3-d]pyrimidine derivatives as potent inhibitors of liver CSC. Structural optimization and anti-CSC screening led to the identification of improved compounds <b>6i</b>, <b>6j</b>, and <b>7e</b>, which significantly inhibited Huh7 sphere formation while exhibiting low toxicity to standard 2D-cultured tumor cells. Notably, compound <b>6i</b> sensitizes both parental and Lenvatinib-resistant HCC cells to Lenvatinib treatment, showing a synergistic interaction. Collectively, these findings establish the pyrrolo[2,3-d]pyrimidine as a promising scaffold for targeting liver CSC and provide a potential combination strategy to overcome Lenvatinib resistance in advanced HCC.</p><p></p>

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Discovery of pyrrolo[2,3-d]pyrimidine derivatives with inhibitory effect on liver cancer stem cell

  • 期刊论文

  • 发表日期：

    2026年6月19日

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  • Xuecong Zhang,
  • Xuechun Chen,
  • Liwei Wang,
  • Yiyuan Chang,
  • Jiaxin Li,
  • Jijian Yang,
  • Dongxuan Ni,
  • Ruihan Zhang,
  • Rong Liu,
  • Weilie Xiao

摘要

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. The malignancy of HCC is closely linked to liver cancer stem cells (CSCs), making the application of anti-CSC drugs a promising therapeutic approach. In this study, we report the discovery of novel pyrrolo[2,3-d]pyrimidine derivatives as potent inhibitors of liver CSC. Structural optimization and anti-CSC screening led to the identification of improved compounds 6i, 6j, and 7e, which significantly inhibited Huh7 sphere formation while exhibiting low toxicity to standard 2D-cultured tumor cells. Notably, compound 6i sensitizes both parental and Lenvatinib-resistant HCC cells to Lenvatinib treatment, showing a synergistic interaction. Collectively, these findings establish the pyrrolo[2,3-d]pyrimidine as a promising scaffold for targeting liver CSC and provide a potential combination strategy to overcome Lenvatinib resistance in advanced HCC.