Biological activity of 4-substituted methoxybenzoyl-aryl-thiazole: an active microtubule inhibitor.

Formation of microtubules is a dynamic process that involves polymerization and depolymerization of αβ-tubulin heterodimers. Drugs that enhance or inhibit tubulin polymerization can destroy this dynamic process, arresting cells in the G(2)/M phase of the cell cycle. Although drugs that target tubulin generally demonstrate cytotoxic potency in the subnanomolar range, resistance due to drug efflux is a common phenomenon among the antitubulin agents. We recently reported a class of 4-substituted methoxybenzoyl-aryl-thiazoles (SMART) that exhibited great in vitro potency and broad spectrum cellular cytotoxicity. Evaluation of the in vitro and in vivo anticancer activities of 3 SMART compounds, SMART-H (H), SMART-F (F), and SMART-OH (OH), with varying substituents at the 4-position of aryl ring, demonstrated that they bind potently to the colchicine-binding site in tubulin, inhibit tubulin polymerization, arrest cancer cells in G(2)/M phase of the cell cycle, and induce their apoptosis. The SMART compounds also equipotently inhibit the growth of parental and MDR-overexpressing cells in vitro, indicating that they can overcome multidrug resistance. In vivo antitumor efficacy studies in human prostate (PC-3) and melanoma (A375) cancer xenograft models demonstrated that SMART-H and SMART-F treatments resulted in %T/C values ranging from 4% to 30%. In addition, in vivo SMART-H treatment for 21 days at the higher dose (15 mg/kg) failed to produce any apparent neurotoxicity. These studies provide the first in vivo evidence and proof-of-concept that SMART compounds are similarly efficacious to currently FDA approved antitubulin drugs for cancer treatment, but they can circumvent P-glycoprotein-mediated drug resistance.