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| Targets |
The target is the proteasome, a large protease complex responsible for degrading ubiquitinated proteins. NIC-0102 is a proteasome inhibitor. By inhibiting the proteasome, it prevents the degradation of certain regulatory proteins, which in turn leads to the specific inhibition of the NLRP3 inflammasome activation pathway and pro-IL-1beta production.
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| ln Vitro |
In J774A.1 and BMDM cells, NIC-0102 (Compound 27) (7.5, 15, 30, 60 nM; 1h) selectively suppresses LPS-induced NLRP3 inflammasome activation [1]. Inducing NLRP3 polyubiquitination, NIC-0102 (7.5, 15, 30, 60 nM; 1h) inhibits the proteasome in LPS-primed J774A.1 cells during their activation step [1]. In LPS-primed J774A.1 cells, NIC-0102 (7.5, 15, 30, 60 nM; 1h) shows inhibitory effects on NF-κB during the priming step of the NLRP3 pathway [1]. In J774A.1 cells, LPS-induced NLRP3-ASC interaction and ASC oligomerization are blocked by NIC-0102 (15, 60 nM; 1h) [1].
In biochemical assays, NIC-0102 exhibits a pIC50 of 7.55 as a proteasome inhibitor, indicating potent and selective inhibition. In cellular models, it specifically inhibits NLRP3 inflammasome activation and suppresses pro-IL-1beta production. The compound shows efficacy at inhibiting the canonical and non-canonical pathways of inflammasome activation. |
| ln Vivo |
NIC-0102 (0.125, 0.25, 0.5 mg/kg; oral administration; every 72 hours for 10 days) showed strong protective effects against DSS-induced acute colitis in mice [1].
In a DSS-induced ulcerative colitis mouse model, NIC-0102 shows potent anti-inflammatory effects in vivo. Oral administration of the compound leads to a reduction in disease activity, which is associated with decreased inflammatory cytokine production in the colon tissue, confirming its in vivo efficacy in a model of inflammatory bowel disease. |
| Enzyme Assay |
Biochemical assays for proteasome inhibition typically use purified 20S proteasome (constitutive or immunoproteasome). The 20S proteasome (1 nM) is incubated with a fluorogenic peptide substrate (e.g., Suc-LLVY-AMC for chymotrypsin-like activity, 100 microM) and varying concentrations of NIC-0102 in assay buffer. The reaction is incubated at 37degC for 60-120 minutes. Fluorescence is measured (Ex/Em=380/460 nm) to determine the IC50 value.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: J774A.1 and BMDM cells (LPS primed) Tested Concentrations: 7.5, 15, 30, 60 nM Incubation Duration: 1 hour Experimental Results: Inhibition of IL-1β release in a dose-dependent manner. Western Blot Analysis[1] Cell Types: J774A.1 cells (LPS primed) Tested Concentrations: 7.5, 15, 30, 60 nM Incubation Duration: 1 hour Experimental Results: Dose-dependent inhibition of release of mature IL-1β and caspase- J774A.1 The presence of 1 p20 subunit in cell supernatants did not affect pro-IL-1β, pro-caspase-1, NLRP3, or ASC in cell lysates. Increased polyubiquitinated NLRP3 protein in a dose-dependent manner and Dramatically increased the amounts of c-Cbl and Cbl-b. At 60 nM, it demonstrated an inhibitory effect on NF-κB subunit p65, phosphorylated p65 and NLRP3 protein, and NF-κB-dependent TNF-α secretion was slightly diminished at this time. Western Blot Analysis[1] Cell Types: J774A.1 cells (LPS primed) Tested Concentrations: 15, 60 nM Incubation Duration: 1 h Experimental Results: Inhibition of LPS- and nigericin-stimulated interaction b The standard cellular protocol uses LPS-primed macrophages. Bone-marrow-derived macrophages (BMDMs) or J774 cells are primed with LPS (100 ng/mL, 3-4 hours). Then, cells are treated with NIC-0102 for 30 minutes before stimulation with ATP (5 mM, 30 min) or nigericin (10 microM, 30 min) to activate the NLRP3 inflammasome. Culture supernatants are collected to measure IL-1beta and IL-18 by ELISA. Cells are lysed, and caspase-1 p20 cleavage is assessed by Western blot. Pro-IL-1beta levels in cell lysates are also measured by Western blot. |
| Animal Protocol |
Animal/Disease Models: Male C57BL/6 mice (6 to 8 weeks old; DSS-induced ulcerative colitis model) [1].
Doses: 0.125, 0.25 and 0.5 mg/kg Route of Administration: po (oral gavage); every 72 hrs (hrs (hours)) for 10 days. Experimental Results: Significant suppression of body weight and fecal occult blood. Colon length was shortened in a dose-dependent manner. Resulting in a dose-dependent decrease in tissue-associated IL-1β concentrations and significant inhibition of pro-IL-1β. Animal/Disease Models: Male C57BL/6 mice (6 to 8 weeks old) [1]. Doses: 0.5 mg/kg (intravenous (iv) (iv)injection); 1 mg/kg (oral) Route of Administration: intravenous (iv) (iv)injection; po (oral gavage); single. Experimental Results: 1.19 pharmacokinetic/PK/PK parameters of NIC-0102 in male C57BL/6 mice [1]. IV (0.5 mg/kg) PO (1 mg/kg) T1/2 (h) 4.73 8.36 Tmax (h) 0.08 0.25 Cmax (ng/mL) 376.6 207.7 AUC0-∞ (h·ng/mL) 448.8 489.2 MRT0- ∞ (h) 6.14 - Vz (L/kg) 7.7 - CL (mL/min/kg) 18.8 - F (%) - 48.1% In a DSS-induced ulcerative colitis mouse model, female C57BL/6 mice are given 2.5-3% dextran sodium sulfate (DSS) in drinking water for 5-7 days to induce colitis. NIC-0102 is administered orally once daily starting from day 0. Body weight loss, stool consistency, and fecal bleeding are monitored daily to calculate the disease activity index (DAI). At the end of the study, colon length is measured, and colon tissues are collected for histological analysis, myeloperoxidase (MPO) activity, and cytokine/chemokine measurements (e.g., IL-1beta, TNFalpha, IL-6) by ELISA. |
| ADME/Pharmacokinetics |
Specific quantitative pharmacokinetic parameters for NIC-0102 are not detailed in the available literature. However, the compound is described as "orally active" and "orally bioavailable," indicating it can be absorbed and achieve sufficient systemic exposure to exert its anti-inflammatory effects in the colon after oral dosing, which is its primary route of administration.
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| Toxicity/Toxicokinetics |
Specific toxicological data for NIC-0102 are not provided in the available literature. As a proteasome inhibitor, its mechanism of action is inherently cytotoxic to rapidly dividing cells. However, the compound's specificity for the NLRP3 pathway may provide a broader therapeutic window than first-generation proteasome inhibitors. Standard toxicological endpoints in animal models would include monitoring body weight, gastrointestinal toxicity, and histopathology.
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| References | |
| Additional Infomation |
NIC-0102 is a research tool for studying the NLRP3 inflammasome pathway and inflammatory bowel disease. Its oral bioavailability and efficacy in a DSS colitis model make it a valuable lead compound for pre-clinical research. As of the latest updates, this compound has not progressed to clinical trials or been approved for sale and is exclusively available for research purposes.
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| Molecular Formula |
C21H25BF2N2O4
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| Molecular Weight |
418.24
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| Exact Mass |
418.187
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| CAS # |
2806031-94-5
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| PubChem CID |
164946740
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
30
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| Complexity |
551
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| Defined Atom Stereocenter Count |
2
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| SMILES |
B([C@@H](NC(=O)[C@@H](NC(=O)C1=C(F)C=CC=C1F)CC1=CC=CC=C1)CC(C)C)(O)O
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| InChi Key |
QTRFWSIBLJYXFJ-ROUUACIJSA-N
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| InChi Code |
InChI=1S/C21H25BF2N2O4/c1-13(2)11-18(22(29)30)26-20(27)17(12-14-7-4-3-5-8-14)25-21(28)19-15(23)9-6-10-16(19)24/h3-10,13,17-18,29-30H,11-12H2,1-2H3,(H,25,28)(H,26,27)/t17-,18-/m0/s1
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| Chemical Name |
[(1R)-1-[[(2S)-2-[(2,6-difluorobenzoyl)amino]-3-phenylpropanoyl]amino]-3-methylbutyl]boronic acid
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3910 mL | 11.9549 mL | 23.9097 mL | |
| 5 mM | 0.4782 mL | 2.3910 mL | 4.7819 mL | |
| 10 mM | 0.2391 mL | 1.1955 mL | 2.3910 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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