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

Abstract

The cytotoxic effects of HMN-176 ((E)-4-[[2-N-[4-methoxybenzenesulfonyl] amino] stilbazole] 1-oxide; a newly synthesized compound, were evaluated and compared with those of the clinically used antitumor agents cis-platinum, adriamycin, etoposide, taxol, and vincristine in 22 human tumor cell lines isolated from various organs. HMN-176 exhibited potent cytotoxicity with IC(50) values in the nM range, and the variance of its cytotoxic efficacy was remarkably small. Drug-resistant cell lines also showed low cross-resistance to HMN-176 corresponding to overall resistance indices of less than 14.3. HMN-214 was synthesized as an oral prodrug because of the poor oral absorption of HMN-176 itself. Pharmacokinetic studies showed that HMN-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 available agents, including cis-platinum, adriamycin, vincristine, and UFT without severe toxicity such as neurotoxicity. Because of its good activity in preclinical trials, HMN-214 has entered Phase I clinical trials in the USA.

Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy

“…HMN-214 is currently under Phase I clinical trials [115, 116]. However, whether it is a bona fide Plk1 inhibitor and, if so, how it inhibits Plk1 need to be clarified.…”

Inhibition of Polo-like Kinase 1 by HMN-214 Blocks Cell Cycle Progression and Inhibits Neuroblastoma Growth

“…HMN-214 [{E)-4-{2-[2-(N-acetyl-N-[4-methoxybenzenesulfonyl] amino) stilbazole]}1-oxide] is a prodrug of HMN-176 ((E)-4-{[2-N-[4-methoxybenzenesulfonyl] amino]-stilbazole}1-oxide) and is developed by Nippon Shinyaku Co. Ltd. (Kyoto, Japan). HMN-214 is currently in the early clinical development phase and has shown potent anti-tumor activity against lung, pancreatic, gastric, prostate, and breast cancer models [ 19 , 20 , 21 , 22 ]. HMN-214 indirectly inhibits PLK1 by altering spatial distribution, resulting in cell cycle arrest at the G2/M phase, with the destruction of the spindle polar bodies followed by DNA fragmentation [ 20 , 22 , 23 , 24 ].…”

Discovery of Novel 2‐N‐Aryl‐Substituted Benzenesulfonamidoacetamides: Orally Bioavailable Tubulin Polymerization Inhibitors with Marked Antitumor Activities

“…Its antitumor activities are mediated by its cytotoxicity via polo-like kinase disturbance, and by MDR1 down-regulation via binding to the B-subunit of the essential transcription factor NF-Y. [25][26][27] It was reported that structural alteration of the benzenesulfonamide scaffold resulted in different antitumor mechanisms. [28] Thus, the discovery that a new structure benzenesulfonamide derivative (designated as AH-487, Scheme 1), screened in-house for its ability to inhibit tumor cell growth, exhibited inhibition of mitosis at the G 2 /M stage with a microtubule-destabilizing mechanism led us to initiate optimization efforts around this novel structure.…”