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

Authors

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

Published in

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents. Jun 19, 2026. Epub Jun 19, 2026.

Abstract

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.

PMID:
42446544
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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