Polo-like kinase 1 (PLK1), a highly conserved member of the polo-like kinase family, functions specifically during mitosis as a regulator of cell division. PLK1 is spatially and temporally enriched at three distinct subcellular locales: the mitotic centrosomes, kinetochores, and the cytokinetic midbody [3]. HMN-214, an oral prodrug of HMN-176, is an inhibitor of PLK1 through altering its cellular spatial localization. The Cmax and AUC of radioactivity after p.o. of 14C-HMN-214 were 17 and 13 times greater, respectively, than those observed after administration of 14C-HMN-176, demonstrating markedly improved oral absorption of HMN-214 compared with HMN-176. In mice bearing WiDr tumors, HMN-214 exhibited a significant antitumor effect with an IR (inhibitory ratios) value of 73.0% at the MTD (maximum tolerated dose) of 20 mg/kg with a loss in body weight of only 2.7 g. In mice bearing PC-3 tumors, HMN-214 was found to be highly active at the MTD of 20 mg/kg, with an IR value of 78.8%. Moreover, the IR value of HMN-214 was 75.2% at 20 mg/kg in mice bearing A549 tumors [4].
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