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

Yuepeng Chen; Liuqiong Meng; Wenze Wang; Liu Ye; Lei Huang; Chenghao Wang; Shuping Wang; Mengyao Li; Yingxin Pei; Shijie Zhang; Yi Zou; Yungen Xu

doi:10.1016/j.ejmech.2023.115846

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. Epub 2023 Oct 7.

Authors

Yuepeng Chen¹, Liuqiong Meng¹, Wenze Wang², Liu Ye², Lei Huang², Chenghao Wang², Shuping Wang³, Mengyao Li², Yingxin Pei², Shijie Zhang², Yi Zou⁴, Yungen Xu⁵

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.

MeSH terms

Cell Line, Tumor
Cell Proliferation
Doublecortin-Like Kinases*
Humans
Intracellular Signaling Peptides and Proteins
Pancreatic Neoplasms* / pathology
Protein Serine-Threonine Kinases
Purines / pharmacology
Pyrimidines / pharmacology
Pyrimidines / therapeutic use
Skeleton / metabolism
Skeleton / pathology

Substances

Doublecortin-Like Kinases
Intracellular Signaling Peptides and Proteins
Protein Serine-Threonine Kinases
Pyrimidines
Purines
DCLK1 protein, human