Design, synthesis and biological evaluation of novel DCLK1 inhibitor containing purine skeleton for the treatment of pancreatic cancer
- Eur J Med Chem. 2023 Dec 5:261:115846. doi: 10.1016/j.ejmech.2023.115846.
- 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
- 2. Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China.
- 3. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China.
- 4. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
- 5. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
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 μM). 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.