Anticancer evaluation of novel chiral tetrahydropyrazolo[1,5-a]pyrimidine derivatives: Inhibitory effects on proliferation and migration of colon cancer cells with high HER2 expression.

In colorectal cancer (CRC), oncogenic activation of the human epidermal growth factor receptor 2 (HER2) is strongly associated with tumor metastasis, poor prognosis, and resistance to anti-EGFR targeted therapies. Currently, there is a lack of tyrosine kinase inhibitors (TKIs) targeting HER2-high-expressing CRC. Current therapeutic approaches face challenges including intertumoral heterogeneity in treatment response and the rapid emergence of drug resistance. Therefore, the development of novel, potent, and selective TKIs for HER2-high-expressing CRC represents a critical unmet medical need. Pyrazolo[1,5-a]pyrimidine is a privileged scaffold widely used in anticancer drug discovery and kinase inhibitor development. Reducing pyrazolo[1,5-a]pyrimidine to the chiral tetrahydropyrazolo[1,5-a]pyrimidine enhances three-dimensional structural complexity and pharmacophore diversity. Based on the chiral tetrahydropyrazolo[1,5-a]pyrimidine scaffold, compound 7 significantly suppresses the proliferation and migration of colon cancer cells with high HER2 expression. It exerts antitumor effects through inhibition of the HER2/AKT/GSK-3β/β-catenin signaling pathway and significantly inhibits tumor growth in LS174T and HCT116 xenograft models in nude mice. These findings provide compelling experimental evidence supporting the development of chiral tetrahydropyrazolo[1,5-a]pyrimidine-based TKIs for HER2-high-expressing CRC.