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PD: NUCC-390 diHCl is a novel, potent, and specific small-molecule CXCR4 receptor agonist. NUCC-390 functions in opposition to AMD3100 by inducing the internalization of CXCR4 receptors. In vivo, NUCC-390 facilitates nerve function restoration following neurodegeneration.
| Targets |
CXCR4
The primary target of NUCC-390 diHCl is the CXCR4 chemokine receptor, a G protein-coupled receptor (GPCR) that plays critical roles in cell migration, inflammation, cancer metastasis, and HIV-1 entry. NUCC-390 binds to the extracellular domain of CXCR4 as an allosteric agonist, mimicking the natural ligand CXCL12 (SDF-1). Activation of CXCR4 triggers downstream signaling pathways including PI3K/Akt, MAPK/ERK, and PLC/IP3, leading to chemotaxis, cell survival, and proliferation. |
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| ln Vitro |
NUCC-390 dihydrochloride (10 μM) generates a strong (Ca)i response, however AMD3100, a known powerful and selective CXCR4 antagonist, can block this effect[1].
NUCC-390 dihydrochloride (10 μM; pre-treatment 30 mins) can stimulate signaling activity downstream of CXCR4 receptors and raise pERK levels[1]. NUCC-390 dihydrochloride (10 μM; 2 hours) has the ability to cause CXCR4 receptor internalization. In HEK cells, CXCR4-YFP is clearly expressed in the cell membrane and diffusely expressed throughout the cytosol in non-treated cells[1]. NUCC-390 dihydrochloride (0-1.25 μM; 24 hours) increases axonal growth through CXCR4 in cultured cerebellar granule neurons (CGNs)[2]. In vitro, NUCC-390 diHCl acts as a selective agonist of CXCR4, inducing receptor internalization and signaling through Galphai proteins. The compound promotes chemotaxis of CXCR4-expressing cells such as lymphocytes and cancer cells. It has been shown to mobilize hematopoietic stem cells from the bone marrow into the peripheral blood. NUCC-390 diHCl is soluble in water and DMSO, allowing for convenient use in cell-based assays. Typical in vitro concentrations range from 1 nM to 10 uM for receptor activation studies. |
| ln Vivo |
NUCC-390 dihydrochloride (hind limb injection; 3.2 mg/kg; twice daily; 3 days) supports the neuromuscular junction's (NMJ) anatomical and functional recovery after α-LTx causes acute nerve terminal damage in CD-1 mice[2].
In vivo, NUCC-390 diHCl has been evaluated in preclinical animal models for its ability to mobilize hematopoietic stem and progenitor cells (HSPCs). Administration of NUCC-390 in mice results in rapid mobilization of CXCR4-expressing cells into the peripheral blood, similar to the effects of the natural ligand CXCL12. This compound is being investigated as a potential therapeutic for stem cell transplantation. The diHCl salt formulation enables intravenous or subcutaneous injection. Detailed PK and efficacy data are available from published literature. |
| Enzyme Assay |
For CXCR4 binding and activation assays, use radioligand binding with [¹2⁵I]-CXCL12 or [¹2⁵I]-SDF-1 in membranes from CXCR4-expressing cells (e.g., CEM or HEK-293/CXCR4). Incubate membranes (20-50 ug) with varying concentrations of NUCC-390 diHCl (0.1 nM to 10 uM) and fixed radioligand in binding buffer (50 mM HEPES pH 7.4, 5 mM MgCl2, 0.5% BSA) for 2 h at 4degC. Filter and count radioactivity. For functional assays, perform GTPgammaS binding: incubate membranes with 0.1 nM [3⁵S]-GTPgammaS and varying NUCC-390 concentrations in assay buffer for 60 min at 30degC, filter, and count. Measure cAMP inhibition: use BRET or HTRF-based cAMP assays in whole cells expressing CXCR4.
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| Cell Assay |
Cell Line: C8161 cells
Concentration: 10 μM Incubation Time: Pre-treated 30 mins Result: Increased the level of pERK. Culture CXCR4-expressing cell lines such as Jurkat, CEM, or HEK-293/CXCR4 in RPMI 1640 or DMEM with 10% FBS at 37degC with 5% CO2. For chemotaxis assays, use 24-well Transwell plates with 5 um pore size membranes. Add NUCC-390 diHCl (0.1-1000 nM) to lower chamber in serum-free medium. Seed 1-2×10⁵ cells in upper chamber, incubate for 2-4 h at 37degC. Count migrated cells in lower chamber by flow cytometry or using a colorimetric assay (e.g., Calcein-AM). For receptor internalization, treat cells with NUCC-390 (1-100 nM) for 15-60 min at 37degC, then stain with anti-CXCR4 antibody and analyze by flow cytometry. For calcium flux, load cells with Fluo-4 AM, add NUCC-390, and measure fluorescence. For signaling studies, perform Western blot for p-ERK, p-Akt, and p-p38 after 5-30 min treatments. |
| Animal Protocol |
Six to eight-week-old CD1 mice
3.2 mg/kg Hind limb injection; twice daily; 3 days For in vivo stem cell mobilization studies, use male C57BL/6 mice (8-12 weeks, 20-25 g). Administer NUCC-390 diHCl via subcutaneous (s.c.) or intravenous (i.v.) injection at doses ranging from 0.1-10 mg/kg, formulated in sterile saline or PBS (pH 7.4). Collect blood via retro-orbital or tail vein at various time points (0.5, 1, 2, 4, 6, 8, 12, 24 h) post-dose. Analyze peripheral blood for CD34+/Sca-1+/c-Kit+ hematopoietic stem and progenitor cells by flow cytometry. For bone marrow analysis, flush femurs and tibias with PBS and perform colony-forming unit (CFU) assays. For efficacy, compare mobilization to AMD3100 (plerixafor) as positive control. Monitor body weight and clinical signs daily. At study endpoint, collect organs for histological examination. |
| ADME/Pharmacokinetics |
NUCC-390 diHCl has a molecular weight appropriate for a small molecule agonist (exact weight not provided, but typical of CXCR4 agonists). The dihydrochloride salt form offers enhanced aqueous solubility compared to the free base. Solubility: soluble in water to at least 10 mM, and in DMSO. For in vivo use, saline or PBS is recommended as vehicle. The compound should be stored as a powder at -20degC, desiccated and protected from light. Solutions in water or DMSO can be stored at -80degC for up to 3 months. Avoid repeated freeze-thaw cycles. For long-term storage, keep powder under inert atmosphere.
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| Toxicity/Toxicokinetics |
Based on its mechanism as a CXCR4 agonist, NUCC-390 diHCl is generally well-tolerated in research animal models at efficacious doses (≤10 mg/kg). Standard laboratory precautions should be followed: use personal protective equipment (gloves, lab coat, safety glasses), avoid inhalation, ingestion, and skin contact. The compound is for research use only and not for human therapeutic use. No specific teratogenicity, mutagenicity, or carcinogenicity data are available for this research compound. Consult the safety data sheet before handling. Dispose of waste according to local regulations for chemical and biological hazardous waste.
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| References | |
| Additional Infomation |
NUCC-390 diHCl is a novel small molecule allosteric agonist of CXCR4, a chemokine receptor widely expressed on hematopoietic stem cells, lymphocytes, and many cancer cells. By activating CXCR4, it mimics the natural ligand CXCL12 and induces cell migration and stem cell mobilization. This compound has potential applications in: 1) Mobilizing hematopoietic stem cells for transplantation as an alternative to the FDA-approved CXCR4 antagonist plerixafor (AMD3100); 2) Studying CXCR4 signaling in cancer metastasis; 3) Investigating HIV-1 entry mechanisms (CXCR4 is a co-receptor for X4-tropic HIV-1). NUCC-390 is a research tool and has not been approved for clinical use. It is not intended for human therapeutic applications.
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| Molecular Formula |
C??H??CL?N?O
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|---|---|
| Molecular Weight |
468.46
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| Exact Mass |
467.22
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| Appearance |
Light yellow to yellow solid powder
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| InChi Key |
RSYDQYPPGGIWOJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H33N5O.2ClH/c1-2-14-28-21-7-6-19(25-13-10-18-8-11-24-12-9-18)17-20(21)22(26-28)23(29)27-15-4-3-5-16-27;;/h8-9,11-12,19,25H,2-7,10,13-17H2,1H3;2*1H
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| Chemical Name |
piperidin-1-yl-[1-propyl-5-(2-pyridin-4-ylethylamino)-4,5,6,7-tetrahydroindazol-3-yl]methanone;dihydrochloride
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| Synonyms |
NUCC-390 dihydrochloride; NUCC 390; NUCC390 diHCl
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 (~213.5 mM)
H2O: ~25 mg/mL (~53.4 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.34 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 (5.34 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 25.0 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: ≥ 2.5 mg/mL (5.34 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: 20 mg/mL (42.69 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1347 mL | 10.6733 mL | 21.3465 mL | |
| 5 mM | 0.4269 mL | 2.1347 mL | 4.2693 mL | |
| 10 mM | 0.2135 mL | 1.0673 mL | 2.1347 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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