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| Targets |
The primary target of NP-G2-044 is fascin, an actin-bundling protein that crosslinks actin filaments into tightly packed bundles. Fascin plays a critical role in the formation of filopodia, lamellipodia, and other actin-based structures involved in cell migration and invasion. Fascin is overexpressed in various cancers and is associated with increased metastatic potential and poor prognosis. By binding to fascin and inhibiting its interaction with actin, NP-G2-044 disrupts actin bundling, thereby reducing cell migration, invasion, and metastasis. The compound's selectivity for fascin over other actin-binding proteins contributes to its specificity.
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| ln Vitro |
MDA-MB-231 tumor cells' motility is inhibited by NP-G2-044, with an IC50 of less than 10 μM. Filopodia development is decreased by NP-G2-044, which also decreases lamellipodia production [1].
In vitro, NP-G2-044 is an inhibitor of the fascin-actin interaction. Its activity is typically measured using actin bundling assays, where the compound's ability to inhibit fascin-mediated actin bundling is assessed by monitoring the increase in light scattering or by visualizing actin bundles by fluorescence microscopy. The compound's effects on cell migration and invasion are assessed using wound healing assays, Transwell migration assays, and Matrigel invasion assays. IC50 values are determined from dose-response curves. |
| ln Vivo |
In mouse models, NP-G2-044 (100 mg/kg; intraperitoneally; once daily for 18 days) prevents the spread of breast tumors [1]. NP-G2-044 binds to myofacundum after terminating at the lateral wall, blocking the development of actin bundles and filopodia α. Tumor cell movement and appropriate cell morphology are facilitated by blocking actin cell remodeling.
In vivo, NP-G2-044 has been studied for its anti-metastatic effects in animal models. By inhibiting fascin-mediated actin bundling, the compound reduces cell migration and invasion, thereby inhibiting tumor metastasis. The compound has been shown to reduce metastasis in various cancer models, including breast cancer, lung cancer, and melanoma. The compound's improved pharmacokinetic properties compared to earlier fascin inhibitors support its potential for therapeutic development. While specific in vivo efficacy data are not extensively detailed in the available literature, its mechanism of action supports its potential as an anti-metastatic agent. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for NP-G2-044 involve actin bundling assays using purified fascin and actin. The compound's ability to inhibit fascin-mediated actin bundling is measured by monitoring the increase in light scattering at 340 nm as actin bundles form. IC50 values are determined from dose-response curves. Binding assays using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) can be employed to measure the affinity of NP-G2-044 for fascin. These assays confirm that NP-G2-044 directly inhibits the fascin-actin interaction.
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| Cell Assay |
In vitro cellular assays for NP-G2-044 are conducted in cancer cell lines that overexpress fascin. Cells are treated with varying concentrations of NP-G2-044, and actin bundling is assessed by fluorescence microscopy using phalloidin staining. Cell migration is assessed using wound healing or Transwell assays. Cell invasion is assessed using Matrigel invasion assays. Cell proliferation is measured using MTT or similar assays. These assays confirm that NP-G2-044 engages its target in a cellular context and produces the expected inhibition of migration, invasion, and actin bundling.
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| Animal Protocol |
Animal/Disease Models: 6-8 weeks old female BALB/c mouse (mouse model bearing 4T1 tumor cells) [1]
Doses: 100mg/kg Mode of Route of Administration: Ip; dynamic changes are damaged, and tumor cell migration and metastasis are inhibited [3]. one time/day for 18 days. Experimental Results: Inhibited the metastasis of 4T1 mouse mammary tumor cells to the lungs. In vivo animal studies for NP-G2-044 are conducted in mouse models of cancer metastasis, such as orthotopic or tail vein injection models. Animals are administered the compound orally or intraperitoneally, and tumor growth and metastasis to distant organs are monitored. The compound's effects on tumor cell migration, invasion, and metastasis are assessed by histopathological examination of primary tumors and metastatic sites. Pharmacokinetic studies are performed to determine the compound's bioavailability, half-life, and tissue distribution. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of NP-G2-044 indicate that it has a molecular weight of 470.95 and a molecular formula of C25H23ClN6O3. The compound is a small molecule with improved pharmacokinetic properties compared to earlier fascin inhibitors. It is soluble in DMSO, facilitating its use in in vitro assays and formulation for in vivo administration. For storage, the powder should be kept under appropriate conditions to maintain stability. Its physicochemical properties suggest that it has reasonable drug-like characteristics for oral administration.
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| Toxicity/Toxicokinetics |
Toxicological information for NP-G2-044 is primarily derived from its use as a research compound in preclinical studies. As a fascin inhibitor, potential on-target effects could include disruption of normal cell migration and tissue remodeling processes, which could affect wound healing and immune function. Comprehensive toxicology studies would be required for therapeutic development, including assessments of wound healing, immune function, and organ toxicity.
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| References | |
| Additional Infomation |
NP-G2-044 is currently undergoing clinical trials (NCT03199586) (Phase I clinical trial of the metastasis inhibitor NP-G2-044 for the treatment of patients with advanced or metastatic solid tumors (including lymphoma)). The Fascin inhibitor NP-G2-044 is an orally effective fascin protein inhibitor with potential antitumor activity. After oral administration, NP-G2-044 targets and binds to fascin, thereby preventing the interaction between fascin and actin filaments, and consequently inhibiting the formation of actin bundles and filopodia. By preventing the reorganization of the actin cytoskeleton, the morphological dynamics required for tumor cell migration and invasion are suppressed, thereby inhibiting tumor cell migration and metastasis. Fibronectin (fascin), the major actin crosslinking protein in filopodia, is upregulated in various metastatic tumor cells, but low or absent in normal adult epithelial cells; its expression is associated with aggressive phenotype, poor prognosis, and shortened survival. Filamentous pseudopodia are finger-like plasma membrane protrusions formed after actin cytoskeleton remodeling. They appear frequently in metastatic tumor cells, and their presence is associated with the invasiveness of tumor cells.
NP-G2-044 is a small molecule inhibitor of the fascin-actin interaction. It disrupts actin bundling, reducing cell migration and invasion, and inhibits tumor metastasis. The compound has improved pharmacokinetic properties compared to earlier fascin inhibitors. NP-G2-044 is not approved for clinical use and is available from research chemical suppliers for preclinical studies. |
| Molecular Formula |
C21H16F3N3O2
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| Molecular Weight |
399.3732
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| Exact Mass |
399.119
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| CAS # |
1807454-59-6
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| PubChem CID |
91844684
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.36±0.1 g/cm3(Predicted)
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| Boiling Point |
470.5±45.0 °C(Predicted)
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| LogP |
4.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
580
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
XLLRLAABUFOJPC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16F3N3O2/c1-13-16(10-11-29-13)20(28)25-19-17-4-2-3-5-18(17)27(26-19)12-14-6-8-15(9-7-14)21(22,23)24/h2-11H,12H2,1H3,(H,25,26,28)
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| Chemical Name |
2-methyl-N-[1-[[4-(trifluoromethyl)phenyl]methyl]indazol-3-yl]furan-3-carboxamide
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| Synonyms |
NPG2-044; NP G2-044; NP-G2-044
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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 |
| 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) |
DMSO : ~100 mg/mL (~250.39 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.26 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 25.0 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: ≥ 2.5 mg/mL (6.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5039 mL | 12.5197 mL | 25.0394 mL | |
| 5 mM | 0.5008 mL | 2.5039 mL | 5.0079 mL | |
| 10 mM | 0.2504 mL | 1.2520 mL | 2.5039 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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