HMN-214

IC50: HMN-176 showed potent cytotoxic activity against several tumor cell lines with an average IC50 of 118 nmol/L

The polo-like kinases (PLK) are a group of highly conserved serine/threonine kinases that serve as regulatory enzymes for mitotic events. HMN-214 is an oral prodrug of HMN-176, a stilbene derivative that interferes with the subcellular spatial location of polo-like kinase-1, a serine/threonine kinase that regulates critical mitotic events.

In vitro: HMN-176 showed potent cytotoxicity, with a mean IC50 of 118 nM. The cytotoxic effecacy of HNM-176 was superior to that of ADM, VP-16 and CDDP, but inferior to that of taxol and VCR. HMN-176 showed less vaiance in log(IC50) than did the reference agents. In addition, judging by its low resistance indices, HMN-176 was more cytotoxic toward the drug-resistant phenotypes of tumor cells than were the other agents tested [1].

In vivo: PK studies showed that HNM-214 was an acceptable oral prodrug of HMN-176. In the in vivo analysis of the schedule-dependency of HMN-214, the repeated administration for over 5 days elicited potent antitumor activity, as expected from the exposure-dependency of the cytotoxicity of HMN-176 and from the cytometric studies. The antitumor activity of HMN-214 against human tumor xenografts was equal or superior to that of clinically avaiable agents, including cis-platinum, adriamycin, vincristine and UFT without severe toxicity such as neurotoxicity [1].

Clinical trial: A phase I pharmacokinetic study indicated that there was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient carcinoembryonic antigen decline in a patient with colorectal cancer was noted [2].

Reference:
[1] Takagi M, Honmura T, Watanabe S, Yamaguchi R, Nogawa M, Nishimura I, Katoh F, Matsuda M, Hidaka H.  In vivo antitumor activity of a novel sulfonamide, HMN-214, against human tumor xenografts in mice and the spectrum of cytotoxicity of its active metabolite, HMN-176. Invest New Drugs. 2003 Nov;21(4):387-99.
[2] Garland LL, Taylor C, Pilkington DL, Cohen JL, Von Hoff DD.  A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors. Clin Cancer Res. 2006 Sep 1;12(17):5182-9.