Synthesis and anti-tumor efficacy of novel 2, 4-diarylaminopyrimidine derivatives bearing N-(3-pyridinylmethyl) urea moiety as anaplastic lymphoma kinase inhibitors.

• 影响指数: 7.088
• 发表时间: Sep 2019 15
• 来源期刊: Eur J Med Chem
• DOI: 10.1016/j.ejmech.2019.05.060
• PMID: 31177074
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 医学
• 作者列表: Chen H,Li R,Ning X,Zhao X,Jin Y,Yin Y

关键词: ALK inhibitor; Anti-proliferation activity; NSCLC; Structure modification

Mesh: Adenocarcinoma of Lung / drug therapy; Anaplastic Lymphoma Kinase / antagonists & inhibitors chemistry; Animals; Antineoplastic Agents / chemical synthesis pharmacology therapeutic use toxicity; Binding Sites; Cell Line, Tumor; Cell Proliferation / drug effects; Drug Stability; Female; Fibroblasts / drug effects; Humans; Lung Neoplasms / drug therapy; Mice, Inbred BALB C; Microsomes, Liver / metabolism; Molecular Docking Simulation; Molecular Structure; Phenylurea Compounds / chemical synthesis pharmacology therapeutic use toxicity; Protein Kinase Inhibitors / chemical synthesis pharmacology therapeutic use toxicity; Pyridines / chemical synthesis pharmacology therapeutic use toxicity; Pyrimidines / chemical synthesis pharmacology therapeutic use toxicity; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for development of various tumor types. In this study, we synthesized a series of novel 2,4-diarylaminopyrimidine derivatives possessing a unique N-(3-pyridinylmethyl)urea moiety as ALK inhibitors. The most promising analog 5m bearing a 3-methoxy-4-morpholinophenyl substituent significantly inhibited proliferation of ALK positive H3122 and Karpas-299 cells with IC50 values about 10 nM, which were comparable with positive control LDK378. Compound 5m suppressed phosphorylation of ALK and its downstream proteins, and showed low cytotoxicity on normal human primary fibroblast cells (BJ cells). The binding mode of 5m was proposed by docking simulation, which explains the important role of N-(3-pyridinylmethyl)urea moiety. Furthermore, compound 5m exhibited favorable liver microsomal stability and significant efficacy in H3122 xenograft mice model. Interestingly, compound 5m also showed broader anti-proliferative activity on other human tumor cell lines, which was different from other ALK inhibitors.