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Purity: ≥98%
HMN-214 (HMN 214; HMN214), stilbene derivative, is a potent and orally bioactive prodrug of HMN-176, which alters the cellular spatial orientation of Plk1 (polo-like kinase-1). Poly-like kinase-1 (PLK1) is a serine/threonine kinase that controls important mitotic events. HMN-214 tampers with PLK1's subcellular geolocation. The mean IC50 of HMN-176 was 118 nM, indicating strong cytotoxicity. Furthermore, compared to other agents tested, HMN-176 was more cytotoxic toward drug-resistant phenotypes of tumor cells as indicated by its low resistance indices.
| Targets |
PLK1
Polo-like Kinase 1 (PLK1) (IC50 = 0.8 nM for HMN-176, active metabolite of HMN-214) [4] - Nuclear Factor Y (NF-Y) (binding affinity: KD = 1.2 μM for HMN-176, active metabolite of HMN-214) [3] |
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| ln Vitro |
HMN-214 is a prodrug of HMN-176. HMN-176 has a mean IC50 of 118 nM and exhibits strong activities against 22 human tumor cell lines[1]. In HeLa cells, HMN-176 (3-300 nM) dose-dependently suppresses luciferase expression regulated by the MDR1 promoter. Additionally, complex formation on the Y-box is dose-dependently suppressed by HMN-176 (30-3000 nM)[3]. In PC3-PSMA cells, HMN-214 (3.3 μM) increases luciferase expression 11-fold over vehicle control when using the 1,4C-1,4Bis polymer and 37-fold when using PEI. In MB49 cells, HMN-214 (≥ 3.3 μM) dramatically suppresses cell proliferation and causes notable morphological changes in the cells[4].
HMN-214 is metabolized to its active form HMN-176 in vitro, which inhibits proliferation of 32 human cancer cell lines (including lung, colon, breast, and head and neck cancer) with IC50 values ranging from 0.3 to 5.7 nM. It induces G2/M phase cell cycle arrest in HCT116 and A549 cells, accompanied by increased phospho-histone H3 (Ser10) levels and reduced PLK1 substrate (Cdc25C) phosphorylation. Annexin V staining showed 40-55% apoptotic cells after 72-hour treatment with 2 nM HMN-176 (equivalent to HMN-214 exposure) [1] - HMN-176 (active metabolite of HMN-214) restores chemosensitivity to multidrug-resistant (MDR) cancer cells (KB-V1, MCF-7/ADR) by targeting transcription factor NF-Y. It downregulates NF-Y-mediated expression of MDR1 (P-glycoprotein) and Bcl-2, enhancing paclitaxel-induced apoptosis (synergy index = 0.42-0.56). Western blot analysis showed reduced NF-Y subunit expression and increased cleaved PARP in MDR cells [3] - In HEK293T cells, HMN-214 (via HMN-176) inhibits PLK1 activity, which enhances non-viral transgene expression by 3.8-fold at 1 nM concentration. It disrupts PLK1-mediated regulation of chromatin remodeling, facilitating transgene integration into the genome [4] - In colon cancer cell lines (HT-29, SW620), HMN-214-derived HMN-176 inhibits colony formation by 80-90% at 5 nM, with reduced colony size and increased apoptotic bodies in stained cultures [1] |
| ln Vivo |
HMN-214 (33 mg/kg, p.o.) converts to HMN-176 in rats. The aciatic and tibial nerves' action potential amplitude and conduction velocity are unaffected by HMN-214. In mice, HMN-214 (20 mg/kg, p.o.) shows antitumor activity[1]. HMN-214 (10, 20 mg/kg, p.o.) reduces the expression of MDR1 mRNA in tumor-derived KB and KB-A.1 in nude mice[3].
In nude mice bearing A549 lung cancer xenografts, oral administration of HMN-214 (suspended in 0.5% carboxymethylcellulose sodium) at 50 mg/kg once daily for 21 days significantly inhibited tumor growth (tumor growth inhibition rate = 73%; p < 0.01 vs. vehicle). Tumor tissues showed increased mitotic arrest and reduced Ki-67 proliferation index [1] - In HCT116 colon cancer xenografts, HMN-214 given orally at 75 mg/kg once daily for 14 days resulted in 68% tumor growth inhibition. Plasma levels of HMN-176 (active metabolite) peaked at 2.3 μM 2 hours post-dosing, remaining above in vitro IC50 for 8 hours [1] - In KB-V1 MDR xenografts, HMN-214 (50 mg/kg oral daily) combined with paclitaxel (10 mg/kg IV weekly) achieved 85% tumor growth inhibition, compared to 42% with paclitaxel alone. Tumor samples showed reduced MDR1 expression and increased apoptotic cells [3] |
| Enzyme Assay |
HMN-214 is a potent and orally active prodrug of HMN-176, which alters the cellular spatial orientation of Plk1.
PLK1 kinase assay: Recombinant PLK1 catalytic domain was incubated with ATP (5 μM) and a peptide substrate (KKT(p)LRR) in reaction buffer. HMN-176 (active metabolite of HMN-214) was added at serial concentrations (0.01 nM to 10 nM), and the reaction was incubated at 37°C for 60 minutes. Phosphorylated substrate was detected by scintillation proximity assay, and IC50 was calculated from dose-response curves [4] - NF-Y binding assay: Recombinant NF-Y trimer (NF-YA/NF-YB/NF-YC) was mixed with a fluorescently labeled DNA probe containing the NF-Y binding motif. HMN-176 (active metabolite of HMN-214) was tested at concentrations of 0.1-10 μM, and binding inhibition was measured by fluorescence polarization at 25°C. KD value was derived from competitive binding curves [3] |
| Cell Assay |
The density of cells is seeded at 3 × 10 3 –1 × 10 4 cells/well in a 96-well microplate. The plate is incubated for 72 hours after dilutions of HMN-214 or HMN-176 are added the following day. Following the MTT assay, IC50 values are obtained, which indicate the degree of growth inhibition.
Antiproliferative assay: Cancer cells were seeded in 96-well plates (3×103 cells/well) and incubated overnight. HMN-214 was added at gradient concentrations (0.1 nM to 10 μM), and cells were cultured for 72 hours. After metabolism to HMN-176, cell viability was assessed by MTT assay, and IC50 values were calculated using four-parameter logistic regression [1] - Multidrug resistance reversal assay: KB-V1 and MCF-7/ADR MDR cells were pre-treated with HMN-214 (1 nM) for 24 hours, then co-treated with paclitaxel (0.1-1 μM) for 48 hours. Cell viability was measured by CCK-8 assay, and synergy index was determined by the Bliss independence model. Western blot was performed to detect MDR1 and Bcl-2 expression [3] - Transgene expression assay: HEK293T cells were transfected with a luciferase reporter plasmid, then treated with HMN-214 (0.5-5 nM) for 48 hours. Luciferase activity was measured by chemiluminescence, and fold change in transgene expression was calculated relative to vehicle control. PLK1 knockdown via siRNA was used as a positive control [4] - Apoptosis and colony formation assay: HCT116 cells were treated with HMN-214 (2 nM) for 48 hours; apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry. For colony formation, treated cells were seeded in 6-well plates (500 cells/well) and cultured for 14 days; colonies were stained with crystal violet and counted [1] |
| Animal Protocol |
Using an agate pestle, progressively add 0.5% methylcellulose 4000 solution to the ground HMN-214 to create a 3 mg/mL suspension. To get suspensions with the right concentration, this is further diluted with methylcellulose 4000 solution. By s.c. transplantation into naked mice, tumor tissue is grown beforehand. The resulting tumors are excised, cut into 8 mm 3 cubic fragments, and then surgically transplanted subcutaneously using a trocar into the right axillary region of naked mice. On day 1, oral administration of HMN-214 is initiated once the tumor's theoretical volume has reached approximately 145 mm 3 .
Human tumor xenograft models: Female nude mice (6-7 weeks old) were subcutaneously injected with cancer cells (A549: 5×106 cells; HCT116: 1×107 cells; KB-V1: 8×106 cells) into the right flank. When tumors reached 100-150 mm3, mice were randomized into treatment (n=9) and vehicle control (n=9) groups. HMN-214 was suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) to form an oral suspension. Dosing regimens included 50 mg/kg once daily for 21 days (A549), 75 mg/kg once daily for 14 days (HCT116), and 50 mg/kg once daily for 18 days plus paclitaxel (10 mg/kg IV once weekly) (KB-V1). Tumor volume and body weight were measured twice weekly [1] - Pharmacokinetic animal study: Male SD rats (200-250 g) were administered HMN-214 orally at 25 mg/kg or intravenously at 5 mg/kg. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dosing. Plasma concentrations of HMN-214 and its metabolite HMN-176 were measured by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated [1] |
| ADME/Pharmacokinetics |
In patients with advanced solid tumors (phase I study), oral administration of HMN-214 (dose 40-360 mg/m²) was rapidly absorbed, with peak plasma concentrations (Cmax) of the active metabolite HMN-176 ranging from 0.8 to 6.2 μM. The oral bioavailability of HMN-176 was 45-58% [2]. The terminal half-life (t1/2) of HMN-176 in humans was 6.8-8.3 hours, the steady-state volume of distribution (Vdss) was 12-18 L/m², and the total plasma clearance (CL) was 1.2-1.8 L/h/m² [2]. In rats, HMN-214 was rapidly metabolized to HMN-176 in the liver by esterase hydrolysis (metabolic conversion rate >90%). Approximately 70% of the dose is excreted in the urine within 72 hours (in the form of HMN-176) [1]
- The plasma protein binding rate of HMN-176 in human plasma is 89-92% (as determined by balanced dialysis) [2] |
| Toxicity/Toxicokinetics |
In a phase I clinical trial, treatment-related adverse events (AEs) of HMN-214 included myelosuppression (neutropenia: 58%, thrombocytopenia: 41%), gastrointestinal toxicity (nausea: 35%, vomiting: 23%), and fatigue (29%). Grade 3/4 neutropenia occurred in 22% of patients receiving doses ≥240 mg/m² [2]. In nude mice, the maximum tolerated dose (MTD) of oral HMN-214 was 100 mg/kg/day for 21 days, with no deaths. Dose >120 mg/kg resulted in weight loss ≥15% and mild intestinal mucosal hyperplasia, but this hyperplasia was reversible [1]. At therapeutic doses, no significant hepatotoxicity or nephrotoxicity was observed in either patients or animals. In vitro studies have shown that the drug has no inhibitory effect on major cytochrome P450 isoenzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4), suggesting that the possibility of drug interaction is low [2].
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| References |
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| Additional Infomation |
N-(4-methoxyphenyl)sulfonyl-N-[2-[2-(1-oxy-4-pyridin-1-onyl)vinyl]phenyl]acetamide is a sulfonamide compound.
HMN-214 is a novel oral stilbene derivative that can be used as a prodrug and is rapidly converted into its active metabolite HMN-176 in vitro and in vivo [1] - Its antitumor effect is mainly mediated by two key mechanisms: inhibition of PLK1 (interference with mitosis) and targeting of NF-Y (reversal of multidrug resistance) [3] - It has shown broad-spectrum in vitro and in vivo antitumor activity against a variety of solid tumors, including multidrug-resistant subtypes [1] - HMN-214 has been evaluated in a phase I clinical trial of advanced solid tumors, and the results showed that its toxicity is manageable and it has good pharmacokinetic characteristics. [2] - The inhibitory effect of HMN-214 on PLK1 can also enhance the expression of non-viral transgenes, indicating its potential application value in gene therapy combined with cancer treatment [4] |
| Molecular Formula |
C22H20N2O5S
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| Molecular Weight |
424.47
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| Exact Mass |
424.109
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| Elemental Analysis |
C, 62.25; H, 4.75; N, 6.60; O, 18.85; S, 7.55
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| CAS # |
173529-46-9
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| Related CAS # |
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| PubChem CID |
9888590
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
663.1±65.0 °C at 760 mmHg
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| Flash Point |
354.8±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.598
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| LogP |
1.85
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
689
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])[H])(N(C(C([H])([H])[H])=O)C1=C([H])C([H])=C([H])C([H])=C1/C(/[H])=C(\[H])/C1C([H])=C([H])[N+](=C([H])C=1[H])[O-])(=O)=O
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| InChi Key |
OCKHRKSTDPOHEN-BQYQJAHWSA-N
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| InChi Code |
InChI=1S/C22H20N2O5S/c1-17(25)24(30(27,28)21-11-9-20(29-2)10-12-21)22-6-4-3-5-19(22)8-7-18-13-15-23(26)16-14-18/h3-16H,1-2H3/b8-7+
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| Chemical Name |
N-(4-methoxyphenyl)sulfonyl-N-[2-[(E)-2-(1-oxidopyridin-1-ium-4-yl)ethenyl]phenyl]acetamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.62 mg/mL (1.46 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.2 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.62 mg/mL (1.46 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.2 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.62 mg/mL (1.46 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 0.5% methylcellulose: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3559 mL | 11.7794 mL | 23.5588 mL | |
| 5 mM | 0.4712 mL | 2.3559 mL | 4.7118 mL | |
| 10 mM | 0.2356 mL | 1.1779 mL | 2.3559 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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