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

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.
Yuepeng Chen 1,  Liuqiong Meng 1,  Wenze Wang 2,  Liu Ye 2,  Lei Huang 2,  Chenghao Wang 2,  Shuping Wang 3,  Mengyao Li 2,  Yingxin Pei 2,  Shijie Zhang 2,  Yi Zou 4,  Yungen Xu 5
Affiliations

Affiliations

  • 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: zouyi@cpu.edu.cn.
  • 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: xyg@cpu.edu.cn.
PMID: 37862816 DOI: 10.1016/j.ejmech.2023.115846
Abstract

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.

Keywords

Antitumor; DCLK1 inhibitor; Drug design; Pancreatic cancer.

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