Tubulin binding compounds that interfere with the dynamic stability of microtubules and disrupt the formation of the mitotic spindle are widely considered one of the most desirable classes of anti-cancer agents. Unfortunately virtually all clinically available tubulin binding agents used for human cancer therapy (paclitaxel, docetaxel, vincristine, vinblastine, etc.) face severe drawbacks, including neurotoxicity, minimal bioavailability and poor solubility, complex synthesis or isolation procedures and, most importantly, the development of drug resistance. Therefore, there exists an urgent need for discovery of novel orally active anti-mitotic compounds that circumvent these liabilities. Employing computer-aided drug design strategies, we have discovered a novel family of 1,3,4-triazole-based small-molecule compounds that target the colchicine binding site of tubulin. A representative subset of five compounds exhibited strong in vitro tubulin polymerization inhibitory activity and cytotoxicity against all parental and multi-drug resistant cancer cell lines tested thus far. These compounds are low molecular weight (
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