Discovery of novel dual tubulin and MMPs inhibitors for the treatment of lung cancer and overcoming drug resistance

Nowadays, hybrid molecule with dual targets activity or effect is regarded as an effective strategy for combating the drug resistance development in cancer therapy. Herein, novel of bifunctional conjugates targeting tubulin and MMPs inhibitors were synthesized. Among them, 15j exhibited robust anticancer activity in vitro and in vivo, with IC50 values of 0.154-0.296 mu M against four human cancer cells and a 74.7 % (@20 mg/kg) tumor growth inhibition in vivo without obvious systemic toxicity. Mechanistic studies indicated that 15j exerted inhibitory effects on both tubulin polymerization, MMP-2 and MMP-9 activity. Moreover, 15j remarkably inhibited cell proliferation, migration and invasion, and accordingly disrupted the NF-kappa B signaling transduction. Furthermore, 15j effectively initiated mitochondria-dependent apoptotic pathway by causing mitochondrial dysfunction, promoting the accumulation of reactive oxygen species, and inducing DNA damage. Collectively, these results demonstrated that 15j, as a tubulin/MMPs dual-targeting inhibitor, has exhibited significant potential for the lung cancer therapy.