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Purity: =100%
HS-1371 is a novel, potent and ATP-competitive RIP3 (receptor-interacting protein kinase 3) inhibitor that is identified by the extensive screening of chemical libraries focused on kinases. A mechanism of action is provided by HS-1371's direct binding to RIP3 in an ATP-competitive and time-independent manner. Further evidence that the substance has a specific inhibitory effect on RIP3-mediated necroptosis via the suppression of RIP3 kinase activity comes from the fact that the compound inhibited TNF-induced necroptosis but did not inhibit TNF-induced apoptosis. For illnesses involving RIP3 hyperactivation, HS-1371 may be used as a preventative or therapeutic agent. Necroptosis is a form of programmed cell death that typically takes place when apoptosis is not present. One of the key players in necroptosis is receptor-interacting protein kinase-3 (RIP3 or RIPK3), and the downstream necroptotic signaling events depend on this protein's kinase activity. The creation of particular RIP3 inhibitors is a promising method for therapeutic use because RIP3 kinase activity has been linked to a number of diseases.
| Targets |
RIP3 (IC50 = 20.8 nM)
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| ln Vitro |
HS-1371 shows an inhibitory effect on S227 auto-phosphorylation of RIP3 at the basal level. It completely inhibits TNF-induced necroptosis signaling, as evidenced by the absence of RIP3 and MLKL phosphorylation in HT-29 cells. By preventing the formation of necrosome complexes, HS-1371's inhibition of RIP3 kinase activity demonstrates disruption of MLKL recruitment. HS-1371 prevents the necroptosis that TNF causes in cells. It prevents necroptotic cell death caused by RIP3 but does not prevent apoptotic cell death[1].
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| Enzyme Assay |
Reaction Biology Corp used radiometric kinase assays ([γ-32P]ATP) to determine all compounds' inhibitory activities toward RIP3. Myelin basic protein (MBP) in a freshly made reaction buffer (20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% BRIJ-35, 0.02 mg/mL BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO) was used to measure the enzymatic activity of RIP3. Each putative RIP3 inhibitor was dissolved in 100% DMSO at particular concentrations, serially diluted with epMotion 5070 in DMSO, and then tested. The reaction buffer received additions of human RIP3 and 20 μM peptide substrate (MBP). The kinase reaction mixture was administered the candidate inhibitor dissolved in DMSO using Acoustic technology (Echo550; nanoliter range), and the reaction mixture was then incubated for 20 min at room temperature. A final ATP concentration of 10 μM and 33P-ATP with a specific activity of 10 μCi/μL were added to the reaction mixture to start the enzymatic reaction. After allowing the reaction mixture to sit at room temperature for two hours, radioactivity was then measured using the filter binding technique. The percentage of remaining kinase activity in relation to the vehicle (dimethyl sulfoxide) reaction was used to calculate the biochemical potency of an inhibitor at a given concentration. The PRISM program was then used to obtain IC50 values and curve fits. Due to its high biochemical potency against numerous kinases, including RIP3, the ATP-competitive inhibitor staurosporine (STSP) was used in this study as a positive control.
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| Cell Assay |
Nec-1 (40 μM), DAB (5 μM), or HS-1371 were pretreated in HT-29 cells for 2 hours before being given TSZ for 4 hours. Anti-RIP3 antibody was used to immunoprecipitate cell lysates.
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| References |
| Molecular Formula |
C24H24N4O
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| Molecular Weight |
384.48
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| Exact Mass |
384.195
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| Elemental Analysis |
C, 74.97; H, 6.29; N, 14.57; O, 4.16
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| CAS # |
2158197-70-5
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| Appearance |
Solid powder
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| SMILES |
CC1=CC=C(C=C1)OC2=C3C=CC(=CC3=NC=C2)C4=CN(N=C4)C5CCNCC5
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| InChi Key |
VPVLPCIBKVWFDT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H24N4O/c1-17-2-5-21(6-3-17)29-24-10-13-26-23-14-18(4-7-22(23)24)19-15-27-28(16-19)20-8-11-25-12-9-20/h2-7,10,13-16,20,25H,8-9,11-12H2,1H3
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| Chemical Name |
4-(4-methylphenoxy)-7-(1-piperidin-4-ylpyrazol-4-yl)quinoline
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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: ≥ 1.67 mg/mL (4.34 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 16.7 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: ≥ 1.67 mg/mL (4.34 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 16.7 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: ≥ 1.67 mg/mL (4.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6009 mL | 13.0046 mL | 26.0092 mL | |
| 5 mM | 0.5202 mL | 2.6009 mL | 5.2018 mL | |
| 10 mM | 0.2601 mL | 1.3005 mL | 2.6009 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.
Identification of HS-1371 as a novel RIP3 kinase inhibitor.. From: HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis.Exp Mol Med.2018 Sep 20;50(9):125. |
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HS-1371 protects cells from TNF-induced necroptosis.. From: HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis.Exp Mol Med.2018 Sep 20;50(9):125. |
Possibility of HS-1371 as a drug for necroptosis-related diseases.. From: HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis.Exp Mol Med.2018 Sep 20;50(9):125. |
HS-1371 had an inhibitory effect on RIP3 kinase activity in various cell lines.. From: HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis.Exp Mol Med.2018 Sep 20;50(9):125. |
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HS-1371 only rescues cells from RIP3-dependent necroptosis.. From: HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis.Exp Mol Med.2018 Sep 20;50(9):125. |
Novel inhibitors can block RIP3 S227 phosphorylation.. From: HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis.Exp Mol Med.2018 Sep 20;50(9):125. |
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