Antitumor effect of 3-(quinolin-2-ylmethylene)-4,6-dimethyl-5-hydroxy-7-azaoxindole down-regulating the Gas6-Axl axis

In this study, a new series of 3-arylidene-4,6-dimethyl-5-hydroxy-7-azaoxindole compounds with a wide range of functional groups were designed, synthesized, and evaluated for their antitumor activity. Among the 35 com-pounds, compound 6-15, with a quinoline moiety, showed cytotoxic IC50 values superior to those of sunitinib against the seven cancer cell lines (MCF-7, MDA-MB-231, HT-29, DU145, U937, A549, and PANC-1). However, its inhibitory activity against receptor tyrosine kinases (VEGFR2, PDGFR beta, c-KIT, FGFR1, FLT3, CSF1R, EGFR, Axl, and Axl mutant) was 100 -3000-fold weaker than that of sunitinib. Interestingly, compound 6-15 exerted a 3.6-fold stronger cytotoxicity than sunitinib in the gemcitabine-resistant PANC-1 cell line and significantly inhibited Axl, which was in contrast with the effect of sunitinib. Nonetheless, both compounds suppressed the expression of growth arrest-specific 6 (Gas6), the ligand of Axl. The inhibitory effect of compound 6-15 on the Gas6-Axl axis was similar to that of Gas6 knockdown by siRNA in PANC-1 cells in terms of apoptosis induction, increase in Bax/Bcl-2 ratio, Axl down-regulation, and PI3K/Akt inhibition. The inhibitory effect of compound 6-15 on tumor growth in mouse tumor models with A549 and PANC-1 xenografts was much greater than that of cisplatin or gemcitabine. Taken together, the current findings demonstrate that compound 6-15 is a promising anticancer drug candidate that acts by inhibiting the Gas6-Axl axis.

Automated summary

A series of 3-arylidene-4,6-dimethyl-5-hydroxy-7-azaoxindole compounds with various functional groups were synthesized and evaluated for their antitumor activity. Compound 6-15, containing a quinoline moiety, exhibited stronger cytotoxicity than sunitinib against multiple cancer cell lines. However, it showed weaker inhibitory activity against receptor tyrosine kinases compared to sunitinib. Compound 6-15 suppressed the expression of Gas6, the ligand of Axl, and demonstrated promising anticancer effects both in vitro and in vivo.