| Size | Price | Stock | Qty |
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| 500mg |
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| 1g |
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| Other Sizes |
Purity: ≥98%
GNE684（GNE-684) is a novel and potent inhibitor of receptor interacting protein 1 (RIP1), it inhibits human RIP1 potently over than mouse and rat with IC50s of 21 nM, 189 nM and 691 nM, respectively. The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases.
| Targets |
Receptor interacting protein 1 (RIP1)
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|---|---|
| ln Vitro |
In multiple human and animal cell lines, GNE684 (20 μM; 20 hours) efficiently suppresses RIP1 kinase-driven cell death[1]. GNE684 (20 μM; 0–60 minutes) inhibits RIP1 autophosphorylation generated by TBZ (2 μM BV6, 20 ng/ml TNF, 20 μM zVAD), as well as RIP3 autophosphorylation and RIP3-mediated phosphorylation of MLKL[1].
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| ln Vivo |
Additionally, in the KPP or KPR (LSL-Kras G12D/+; p16/p19 fl/wt; Trp53 R270H/wt; Pdx1-cre) PDAC models, GNE684 had no effect on overall survival or tumor growth[1]. Intestinal epithelial cells (IECs) that lack NEMO are the source of colitis and ileitis, which are inhibited by GNE684 (50 mg/kg; po twice daily)[1].
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: L929 cells, Jurkat cells, MEFs Tested Concentrations: 20 μM Incubation Duration: 20 hrs (hours) Experimental Results: Inhibited RIP1 kinase driven cell death effectively in several human and mouse cell lines. Western Blot Analysis[1] Cell Types: HT-29 cells, J774A.1 cells Tested Concentrations: 0 μM, 20 μM Incubation Duration: 0 minute, 15 minutes, 60 minutes Experimental Results: Disrupted TBZ (2 μM BV6, 20 ng/ml TNF, 20μM zVAD)-induced RIP1 autophosphorylation, interactions between RIP1 and RIP3, RIP3 autophosphorylation, and phosphorylation of MLKL by RIP3. |
| Animal Protocol |
Animal/Disease Models: Nemofl/fl Villin.creERT2 mice (NEMO IEC-KO)[1]
Doses: 50 mg/kg Route of Administration: Oral administration; twice (two times) daily; from days 2–6 treated with tamoxifen Experimental Results: Almost completely protected the NEMO-deficient intestines from colitis and ileitis. |
| References | |
| Additional Infomation |
The kinase RIP1 participates in multiple signaling pathways, regulates inflammatory responses, and can induce apoptosis and necroptosis. Its kinase activity is associated with various inflammatory diseases, neurodegenerative diseases, and neoplastic diseases. This study investigated the effects of gene knock-in expression of the catalytically inactive RIP1 D138N mutant in mice and pharmacological inhibition of RIP1 using the potent murine inhibitor GNE684. Results showed that RIP1 inhibition alleviated collagen antibody-induced arthritis and prevented skin inflammation caused by Sharpin gene mutations and colitis caused by Nemo gene deletion in intestinal epithelial cells. Conversely, RIP1 inhibition had no effect on tumor growth or survival in a mutant Kras-driven pancreatic tumor model, nor did it reduce lung metastases in a B16 melanoma model. In summary, our data highlight the role of RIP1 kinase activity in certain inflammatory disease models, but raise questions about its association with tumor progression and metastasis.
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| Molecular Formula |
C23H24N6O3
|
|---|---|
| Molecular Weight |
432.475064277649
|
| Exact Mass |
432.190988
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| Elemental Analysis |
C, 63.88; H, 5.59; N, 19.43; O, 11.10
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| CAS # |
2438637-64-8
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| PubChem CID |
138377384
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| Appearance |
Typically exists as solid at room temperature
|
| LogP |
2.4
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| SMILES |
N1=C(C(N[C@H]2C(=O)N(C)C3C=NC(OC)=CC=3CC2)=O)N=C2CC[C@H](C3=CC=CC=C3)N12
|
| InChi Key |
JXFYROJRZJPKTQ-IRXDYDNUSA-N
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| InChi Code |
InChI=1S/C23H24N6O3/c1-28-18-13-24-20(32-2)12-15(18)8-9-16(23(28)31)25-22(30)21-26-19-11-10-17(29(19)27-21)14-6-4-3-5-7-14/h3-7,12-13,16-17H,8-11H2,1-2H3,(H,25,30)/t16-,17-/m0/s1
|
| Chemical Name |
(5S)-N-[(3S)-7-methoxy-1-methyl-2-oxo-4,5-dihydro-3H-pyrido[3,4-b]azepin-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide
|
| Synonyms |
GNE-684; GNE 684; GNE684; 2438637-64-8; CHEMBL5208359; (5S)-N-[(3S)-7-Methoxy-1-methyl-2-oxo-4,5-dihydro-3H-pyrido[3,4-b]azepin-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide; (5S)-N-[(3S)-7-methoxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-3-yl]-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide; rel-(S)-N-((S)-7-Methoxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide; SCHEMBL25798914; GTPL13107; GNE684
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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 | 2.3122 mL | 11.5612 mL | 23.1225 mL | |
| 5 mM | 0.4624 mL | 2.3122 mL | 4.6245 mL | |
| 10 mM | 0.2312 mL | 1.1561 mL | 2.3122 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.
Products are for research use only; We do not sell to patients
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