Tubulin Polymerization Inhibitor AEZS 112

In vitro: ZEN-012 has shown potent in vitro anti-proliferative activity at nanomolar concentrations against human tumor cell lines of different origin. ZEN-012 is active in tumor cell lines which are resistant to cisplatin and doxorubicin as well as to tubulin inhibitors such as vincristine and paclitaxel. Furthermore, it was shown thatZEN-012 is a catalytic inhibitor of the enzyme topoisomerase II with the same potency as amsacrine. In vivo: Given orally once or twice weekly, ZEN-012 proved to be a potent inhibitor of in vivo tumor growth in mammary, lung, renal, colon, melanoma xenograft models as well as in leukemia cancer models at well tolerated doses (16-40mg/kg). Furthermore,ZEN-012 showed good safety and toxicity profiles in a series of rodent and non-rodent studies.

Mode of action studies revealed that the compound ZEN-012 inhibits the polymerization of ß-tubulin in low micromolar concentrations. Competition studies suggest that ZEN-012 interacts with the same binding site on microtubules as colchicine. ZEN-012 destroys the mitotic spindles of the cancer cells, arrests the cancer cells in G2/M phase at low concentrations, mediates DNA fragmentation via inhibition of topoisomerase II and induces apoptosis via various mechanisms.