Structural modifications of indolinones bearing a pyrrole moiety and discovery of a multi-kinase inhibitor with potent antitumor activity.

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, PDGFRα/β, 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.