期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 28, 期 11, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115486
关键词
Structural modification; Multi-kinase inhibitor; Antitumor activity
资金
- China Postdoctoral Science Foundation [2018M633720]
- Liaoning Revitalization Talents Program [XLYC1808037]
Structural modifications of compound 2, an angiokinase inhibitor reported by our group were performed, which led to the discovery of methyl (Z)-3-(((4-(2-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrrol-1-yl)phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (7h). Compound 7h exhibited excellent inhibitory activity against angiokinases including VEGFR-1/2/3, PDGFR alpha/beta, and FGFR-1, as well as LYN and c-KIT kinases. At the cellular level, compound 7h significantly attenuated phosphorylation of AKT and ERK proteins, potently inhibited colony formation of HT-29, MKN74, and HepG2 cancer cells, and induced cell apoptosis. Upon incubation with human liver microsome, 7h exhibited comparable metabolic stability to nintedanib. Compound 7h has emerged as a promising lead compound for future drug design.
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