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HMN-214

Description of HMN-214:  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.

Current developer:   Nippon Shinyaku Co., Ltd

Phase I trials of HMN-214: Thirty-three patients were enrolled onto four dosing cohorts of HMN-214 from 3 to 9.9 mg/m2/d using a continuous 21-day dosing schedule every 28 days, with pharmacokinetic sampling during cycle 1. RESULTS:  A severe myalgia/bone pain syndrome and hyperglycemia were dose-limiting toxicities at 9.9 mg/m2/d. A dose reduction and separate enrollment by pretreatment status (lightly versus heavily pretreated) was undertaken, with one dose-limiting toxicity (grade 3 bone pain) at 8 mg/m2/d. The maximum tolerated dose was defined as 8 mg/m2/d for both treatment cohorts. Dose-proportional increases were observed in AUC but not Cmax. There was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease as best tumor response, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient decline in carcinoembryonic antigen in a patient with colorectal cancer was noted. CONCLUSIONS: The maximum tolerated dose and recommended phase II dose of HMN-214 when administered on this schedule was 8 mg/m2/d regardless of pretreatment status. Further development of HMN-214 will focus on patient populations for which high expression of polo-like kinase-1 is seen (i.e., prostate and pancreatic cancer patients). (source: Clin Cancer Res. 2006 Sep 1;12(17):5182-9.).

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2. Low, Jonathan; Chakravartty, Arunava; Blosser, Wayne; Dowless, Michele; Chalfant, Christopher; Bragger, Patty; Stancato, Louis. Phenotypic fingerprinting of small molecule cell cycle kinase inhibitors for drug discovery. Current Chemical Genomics (2009), 3 13-21. CODEN: CCGUAQ ISSN:1875-3973. CAN 152:254294 AN 2009:623851

3. Xiang, Youbin; Jaspersen, Sue; Florens, Laurence; Smith, Sarah Kendall; Hawley, R. Scott. Inhibition of Polo kinase by Matrimony protein maintains G2 arrest in the meiotic cell cycle. U.S. Pat. Appl. Publ. (2009), 41 pp. CODEN: USXXCO US 2009123934 A1 20090514 CAN 150:533852 AN 2009:587922

4. Hu, Laixing; Li, Zhou-rong; Wang, Yue-ming; Jiang, Jian-dong; Boykin, David W. Structure-activity relationships of novel pyridinyl and pyrimidinyl carbazole sulfonamides as antiproliferative agents. Abstracts, 58th Southeast Regional Meeting of the American Chemical Society, Augusta, GA, United States, November 1-4 (2006), SRM06-194. CODEN: 69INUY AN 2006:1190723

5. Palazzo, Robert E. Marine invertebrate gametes and embryos as an assay system for therapeutic screening. U.S. Pat. Appl. Publ. (2006), 12pp. CODEN: USXXCO US 2006240402 A1 20061026 CAN 145:432189 AN 2006:1123520

6. Garland, Linda L.; Taylor, Charles; Pilkington, Deborah L.; Cohen, Jan L.; Von Hoff, Daniel D. 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. Clinical Cancer Research (2006), 12(17), 5182-5189. CODEN: CCREF4 ISSN:1078-0432. CAN 146:454294 AN 2006:899334

7. Medina-Gundrum, Leticia; Cerna, Cesario; Gomez, Lionel; Izbicka, Elzbieta. Investigation of HMN-176 anticancer activity in human tumor specimens in vitro and the effects of HMN-176 on differential gene expression. Investigational New Drugs (2005), 23(1), 3-9. CODEN: INNDDK ISSN:0167-6997. CAN 142:290700 AN 2004:930695

8. Tanaka, Hideki; Ohshima, Nobuko; Ikenoya, Mami; Komori, Kinuyo; Katoh, Fumitaka; Hidaka, Hiroyoshi. HMN-176, an Active Metabolite of the Synthetic Antitumor Agent HMN-214, Restores Chemosensitivity to Multidrug-Resistant Cells by Targeting the Transcription Factor NF-Y. Cancer Research (2003), 63(20), 6942-6947. CODEN: CNREA8 ISSN:0008-5472. CAN 140:174617 AN 2003:845423

9. Takagi, Manabu; Honmura, Takuya; Watanabe, Shuuji; Yamaguchi, Reiko; Nogawa, Masaki; Nishimura, Ikumi; Katoh, Fumitaka; Matsuda, Masato; Hidaka, Hiroyoshi. 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. Investigational New Drugs (2003), 21(4), 387-399. CODEN: INNDDK ISSN:0167-6997. CAN 141:16960 AN 2003:833144

10. Bayes M; Rabasseda X; Prous J R Gateways to clinical trials. Methods and findings in experimental and clinical pharmacology (2004), 26(8), 639-63. Journal code: 7909595. ISSN:0379-0355. PubMed ID 15605126 AN 2004629312