Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2
Autor: | Liping Hu, Xupeng Yue, Xin Xu, Xingwei Xu, Huan He, Guowei Gong, Yuting Zhou, Tao Chen, Baohui Qi, Ying Yang |
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Rok vydání: | 2019 |
Předmět: |
Molecular model
Cabozantinib Pyridines Clinical Biochemistry Pharmaceutical Science Apoptosis Pharmacology 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Drug Discovery Humans Urea Structure–activity relationship Anilides Cytotoxicity Protein Kinase Inhibitors Molecular Biology Cell Proliferation Binding Sites 010405 organic chemistry Chemistry Kinase Organic Chemistry Vascular Endothelial Growth Factor Receptor-2 In vitro Protein Structure Tertiary 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry fms-Like Tyrosine Kinase 3 Drug Design Cancer cell Molecular Medicine Thiazolidinediones |
Zdroj: | Bioorganic & Medicinal Chemistry. 27:2127-2139 |
ISSN: | 0968-0896 |
Popis: | A series of novel thiazolidine-4-one urea analogues were designed, synthesized and biologically evaluated. The structure-activity relationship (SAR) at several positions of the scaffolds was investigated and its binding mode was analyzed by molecular modeling studies. Compound 17b proved to be the most potent one, and IC50 values against A549 and HT-29 cancer cell lines were 0.65 μM and 0.11 μM, respectively. The results of kinase profile demonstrated that compound 17b is a multikinase inhibitor that potently inhibits FLT3 (IC50 = 8.6 nM) and VEGFR2 (IC50 = 18.7 nM). The results of real-time live-cell imaging indicated that compound 17b showed excellent cytotoxicity and anti-proliferative activity against HT-29 cancer cells in a time- and dose-dependent manner, which was significantly potent than that of Cabozantinib. In addition, in vitro antitumor activity was associated with inducing cancer cell apoptosis and suppression of cancer cell migration. |
Databáze: | OpenAIRE |
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