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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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HMN-214 (IVX-214) is a potent inhibitor of Polo-like kinase (Plk)1 with IC50 of 118 nM. |
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Targets
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Polo-like kinase (Plk)1 |
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IC50 |
118 nM [1] |
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In Vitro
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HMN-214 is an oral prodrug that is rapidly converted to HMN-176. The in vitro data of HMN-214 are scarce. However, HMN-176, active metabolite of HMN-214, shows potent and broad-spectrumanti-tumor activity against various cancer cells, including HeLa, PC-3, DU-145, MIAPaCa-2, U937, MCF-7, A549, and WiDr, with a mean IC50 value of 118 nM. HMN-176 is also cytotoxic to drug-resistant human and murine cell lines, including P388/CDDP, P388/VCR, K2/CDDP, and K2/VP-16, with IC50 values ranging from 143 nM–265 nM. In HeLa cells, HMN-176 (3 μM) blocks cell cycle at G2/M phase. [1]In Doxorubicin-resistant K2/ARS cells, HMN-176 inhibits cell growth with an IC50 value of 2 μM. HMN-176 (3 μM) down-regulates the expression of the multidrug resistance gene (MDR1), due to the disturbance of NF-Y transcription factor binding to the MDR1 promoter. [2]In human RPE1 and CFPAC-1 cells, HMN-176 (2.5 μM) delays satisfaction of the spindle assembly checkpoint. HMN-176 (250 nM–2.5 μM) inhibits meiotic spindle assembly and aster formationin Spisula oocytes. HMN-176 (2.5 μM) also inhibits aster microtubule formation from human centrosomes. These results indicate that the anti-tumor activity of HMN-176 is at least partially via disrupting centrosome-mediated MT assembly during mitosis. [3] |
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In Vivo
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HMN-214 is an oral pro-drug of HMN-176 with improved oral absorption. HMN-214 (30 mg/kg) triggers no obvious neurotoxicity in mice. In mouse xenograft model of PC-3, A549, and WiDr cells, HMN-214 (10 mg/kg–20 mg/kg) inhibits tumor growth. [1]In nude mice model bearing multidrug-resistant KB-A.1 cells, HMN-214 (10 mg/kg–20 mg/kg) significantly suppresses MDR1 mRNA expression. [2] |
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Clinical Trials
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Features
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Protocol
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Cell Assay
[1]
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| Cell Lines |
HeLa, PC-3, DU-145, MIAPaCa-2, U937, MCF-7, A549, and WiDr cells |
| Concentrations |
0–10 μM, dissolved in DMSO |
| Incubation Time |
72 hours |
| Methods |
Cells are seeded into a 96-well microplate at a density of 3 × 103–1 × 104 cells/well. Dilutions of HMN-214 or HMN-176 are added the next day and the plate is incubated for 72 hours. The inhibition of growth is measured by the MTT assay and IC50 values are then obtained. |
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Animal Study
[1]
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| Animal Models |
Male BALB/c nude mice bearing xenografts of PC-3, A549, and WiDr cells |
| Formulation |
Dissolved in 0.5% methylcellulose |
| Doses |
10 mg/kg–20 mg/kg |
| Administration |
Oral gavage on a QD × 28 schedule |
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References |
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[1] Takagi M, et al. Invest New Drugs, 2003, 21(4), 387-399.
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[2] Tanaka H, et al. Cancer Res, 2003, 63(20), 6942-6947.
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[3] DiMaio MA, et al. Mol Cancer Ther, 2009, 8(3), 592-601.
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