Design, synthesis and biological evaluation of novel DCLK1 inhibitor containing purine skeleton for the treatment of pancreatic cancer

Pancreatic cancer is a highly lethal form of malignancy that continues to pose a significant and unresolved health challenge. Doublecortin-like kinase 1 (DCLK1), a serine/threonine kinase, is found to be overexpressed in pancreatic cancer and holds promise as a potential therapeutic target for this disease. However, few potent inhibitors have been reported currently. Herein, a series of novel purine, pyrrolo [2,3-d]pyrimidine, and pyrazolo [3,4-d] pyrimidine derivatives were designed, synthesized, and evaluated their biological activities in vitro. Among them, compound I-5 stood out as the most potent compound with strong inhibitory activity against DCLK1 (IC50 = 171.3 nM) and remarkable antiproliferative effects on SW1990 cell lines (IC50 = 0.6 mu M). Notably, I-5 exhibited higher in vivo antitumor potency (Tumor growth inhibition value (TGI): 68.6 %) than DCLK1-IN-1 (TGI: 24.82 %) in the SW1990 xenograft model. The preliminary mechanism study demonstrated that I-5 not only inhibited SW1990 cell invasion and migration, but also decreased the expression of prominin-1 (CD133) and cluster of differentiation 44 (CD44), which are considered as differentiation markers for SW1990 stem cells. All the results indicated that I-5, a novel DCLK1 inhibitor, shows promise for further investigation in the treatment of pancreatic cancer.

Automated summary

Pancreatic cancer is a deadly malignancy that poses a significant health challenge. Doublecortin-like kinase 1 (DCLK1) has been identified as a potential therapeutic target for this disease, but few inhibitors have been reported. In this study, a series of novel compounds were designed and synthesized, and their biological activities were evaluated. Compound I-5 showed potent inhibitory activity against DCLK1 and antiproliferative effects on cancer cells. It also exhibited higher antitumor potency than a known inhibitor in an animal model. Furthermore, I-5 inhibited cell invasion and migration and decreased the expression of stem cell markers. These findings suggest that I-5 holds promise for further investigation in the treatment of pancreatic cancer.