ZIO-301 (Indibulin) a novel tubulin polymerization inhibitor has potent anti-tumor activity and a distinct tubulin binding site Free

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ZIO-301 (N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid; also called Indibulin and D-24851) is a novel synthetic anti-mitotic agent that binds tubulin, destabilizes microtubulin polymerization and arrests tumor cell growth at the G2/M phase. Microtubulins are well-established targets for anti-cancer drug development and tubulin binding drugs such as taxanes and vinca alkaloids are currently widely used to treat cancer. While taxanes stabilize tubulin polymers, ZIO-301, vinca alkaloids and colchicines destabilize polymerization. In addition, each class of these anti-mitotic drugs has distinct tubulin binding sites. The distinct tubulin binding site of ZIO-301 might be the reason for the lack of neurotoxicity observed in animals and in Phase I clinical trials. ZIO-301 is orally active in a panel of human, murine and rat tumor cell lines in vitro and in xenografts. ZIO-301 is also active in multidrug resistant tumor cell lines. ZIO-301 in its oral formulation is currently in Phase I clinical trials.

To further define the putative tubulin binding site of ZIO-301, 3H- ZIO-301 was incubated with purified bovine brain tubulin in the presence or absence of various tubulin binding agents. ZIO-301 binding to tubulin occurred in the absence of proteins typically associated with microtubules. Binding was nearly completely inhibited by unlabeled colchicine, nocodazole or podophyllotoxin but not by paclitaxel or vinblastine. However, 3H- colchicine binding to tubulin was only inhibited about 40% by excess ZIO-301. These data indicate that ZIO-301 binds to a site that overlaps with the colchicine binding site.

To extend earlier observations of ZIO-301 anti-tumor activity, ZIO-301 was tested in diverse cancer models including murine renal cell carcinoma (RENCA), BMD induced mammary carcinoma in rats, human ovarian xenograft (SK-OV-3), human prostate cancer xenograft (PC-3), A431 human vulvar squamous cell carcinoma xenograft, and U 87 human glioblastoma xenograft. In all models ZIO-301 showed strong and statistically significant anti-tumor activity. Importantly, at curative doses animals showed no signs of neurotoxicity or loss of body weight typically associated with taxanes or vinca alkaloids. These differences in pharmacodynamics and safety of ZIO-301 potentially make ZIO-301 an effective anti-cancer drug.