期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 154, 期 -, 页码 9-28出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.05.005
关键词
FGFR; VEGFR; Synergistic effect; Tumor growth inhibition; Lucitanib
资金
- National Natural Science Foundation of China [81703327, 81773565, 81430080, 81773762]
- International Cooperative Program of the Chinese Academy of Sciences [GJHZ1622]
- Key Program of the Frontier Science of the Chinese Academy of Sciences [160621]
- Shanghai Commission of Science and Technology [16XD1404600, 14431900400]
- Personalized Medicines - Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020000]
Starting from the phase II clinical FGFR inhibitor lucitanib (2), we conducted a medicinal chemistry approach by opening the central quinoline skeleton coupled with a scaffold hopping process thus leading to a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives. Compound 25a was identified to show selective and equally high potency against FGFR1/2 and VEGFR2 with IC50 values less than 5.0 nM. Significant antiproliferative effects on both FGFR1/2 and VEGFR2 aberrant cancer cells were observed. In the SNU-16 xenograft model, compound 25a showed tumor growth inhibition rates of 25.0% and 81.0% at doses of 10 mg/kg and 50 mg/kg, respectively, with 5% and 10%body weight loss. In view of the synergistic potential of FGFs and VEGFs in tumor angiogenesis observed in preclinical studies, the FGFR/VEGFR2 dual inhibitor 25a may achieve better clinical benefits. (C) 2018 Elsevier Masson SAS. All rights reserved.
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