期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 109, 期 -, 页码 1-12出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.12.033
关键词
N-Phenylquinazolin-4-amine hybrid; VEGFR-2; HDAC; Dual inhibitor
资金
- National Natural Science Foundation of China [21102182]
- Natural Science Foundation of Jiangsu Province [BK2012760]
- Research Fund of young scholars for the Doctoral Program of Higher Education of China [20110096120008]
- College Students Innovation Project for the R&D of Novel Drugs [J1030830]
- Youth development projects of Army Medical Technology [15QNP021]
A single agent that simultaneously inhibits multiple targets may offer greater therapeutic benefits in cancer than single-acting agents through interference with multiple pathways and potential synergistic action. In this work, a series of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties were designed and identified as dual VEGFR-2/HDAC inhibitors. Compound 6fd exhibited the most potent inhibitory activity against HDAC with IC50 of 2.2 nM and strong inhibitory effect against VEGFR-2 with IC50 of 74 nM. It also showed the most potent inhibitory activity against a human breast cancer cell line MCF-7 with IC50 of 0.85 mu M. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the active binding sites of VEGFR-2 and HDLP ((Histone Deacetylase-Like Protein), which demonstrates that compound 6fd is a potential agent for cancer therapy deserving further researching. (C) 2015 Elsevier Masson SAS. All rights reserved.
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