Abstract
IMB5046 is a nitrobenzoate microtubule inhibitor we reported previously. During screening of its structural analogues, we identified a novel compound IMB5476 with increased aqueous solubility. Here, its antitumor activity and the underlying mechanism were investigated. IMB5476 disrupted microtubule networks in cells and arrested cell cycle at G2/M phase. It inhibited purified tubulin polymerization in vitro. Competition assay indicated that it bound to tubulin at the colchicine pocket. Further experiments proved that it induced cell death by mitotic catastrophe and apoptosis. Notably, it was a poor substrate of P-glycoprotein and exhibited potent cytotoxicity against drug-resistant tumor cells. In addition, IMB5476 could inhibit angiogenesis in vitro. IMB5476 also inhibited the growth of drug-resistant KBV200 xenografts in mice. Conclusively, our data reveal a novel nitrobenzoate microtubule inhibitor with improved aqueous solubility and can overcome multidrug resistance.
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