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Purity: ≥98%
GSK-963 (also known as GSK'963 or GSK963), is a potent and selective RIP1 kinase inhibitor. NSC59984 is a novel and potenl p53 activator with potential anticancer activity. It works by causing the degradation of mutant p53 protein and the activation of p73.GSK'963 inhibits RIP1-dependent cell death with an IC50 of between 1 and 4 nM in human and murine cells, making it significantly more potent than Nec-1 (a well-known RIP1 kinase inhibitor). In addition to having an inactive enantiomer, GSK'962, that can be used to confirm on-target effects, GSK'963 has a >10 000-fold selectivity for RIP1 over 339 other kinases. The enhanced in vitro potency of GSK'963 also translates in vivo, where GSK'963 at matched doses to Nec-1 significantly increases protection from hypothermia in a model of TNF-induced sterile shock. Together, we think that GSK'963 is a next-generation tool for examining RIP1 function both in vitro and in vivo, and it should help to clarify how RIP1 contributes to disease pathogenesis, as it is currently understood to do.
| Targets |
RIP1 kinase (IC50 = 29 nM)
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| ln Vitro |
GSK-963 inhibits RIP1-dependent cell death in human and murine cells with an IC50 range of 1 to 4 nM[1].
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| ln Vivo |
GSK-963 is a powerful inhibitor of a lethal shock caused by TNF+zVAD. In comparison to Nec-1, GSK-963 would maintain blood concentrations above the level necessary for 90% inhibition of RIP1 activity for a longer period of time at 2 mg/kg.
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| Enzyme Assay |
Compound potency against RIP1 kinase activity was determined using an ADP-Glo luminescence assay, which measures the conversion of ATP to ADP as previously described. In brief, the primary reaction consisted of 10 nM GST-RIPK1 (1–375) and 50 μM ATP in 50 mM HEPES pH 7.5, 50 mM NaCl, 30 mM MgCl2, 1 mM DTT, 0.5 mg/ml BSA, and 0.02% CHAPS. Five microliter of enzyme and 5 μl of ATP were added to the plate at twice the final assay concentration and incubated at room temperature for 4 h. The luminescence was measured on a plate reader. Test compound inhibition was expressed as percent inhibition of internal assay controls.
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| Cell Assay |
For immunoblot analysis, BMDM are stimulated with 50 ng/ml TNF for 5 and 15 minutes after being pretreated for 30 minutes with GSK'963 (100 nM), GSK'962 (100 nM), or Nec-1 (10 μM). Lysates made with protease and phosphatase inhibitors in 1× Cell Lysis Buffer are separated on 4-12% SDS-PAGE and blotted onto nitrocellulose membrane. IκB, phospho-IκB, and tubulin are probed as loading controls on blots.
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| Animal Protocol |
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| References |
| Molecular Formula |
C14H18N2O
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| Molecular Weight |
230.31
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| Exact Mass |
230.1419
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| Elemental Analysis |
C, 73.01; H, 7.88; N, 12.16; O, 6.95
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| CAS # |
2049868-46-2
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| Related CAS # |
GSK962;2049872-86-6
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| Appearance |
Solid powder
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| SMILES |
CC(C)(C)C(=O)N1[C@@H](CC=N1)C2=CC=CC=C2
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| InChi Key |
NJQVSLWJBLPTMD-LBPRGKRZSA-N
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| InChi Code |
InChI=1S/C14H18N2O/c1-14(2,3)13(17)16-12(9-10-15-16)11-7-5-4-6-8-11/h4-8,10,12H,9H2,1-3H3/t12-/m0/s1
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| Chemical Name |
2,2-dimethyl-1-[(3S)-3-phenyl-3,4-dihydropyrazol-2-yl]propan-1-one
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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: 2.5 mg/mL (10.85 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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. Solubility in Formulation 2: ≥ 2.5 mg/mL (10.85 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 | 4.3420 mL | 21.7099 mL | 43.4197 mL | |
| 5 mM | 0.8684 mL | 4.3420 mL | 8.6839 mL | |
| 10 mM | 0.4342 mL | 2.1710 mL | 4.3420 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.
GSK′963A is a potent and selective inhibitor of RIP1 kinase. (a) Chemical structures of GSK′963A (active analog), GSK′962A (inactive analog) and Necrostatin-1. (b) Dose–response curves for GSK′963, GSK′962 and Nec-1 in the FP binding assay evaluating the affinity of compounds for RIP1 (ATP-binding pocket).Cell Death Discov.2015 Jul 27;1:15009. |
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 GSK′963A is highly potent in human and mouse cell-based assays and selective for inhibition of necroptosis. (a–d) Dose–response curves for GSK′963, GSK′962 and Nec-1 in cell-based assays.Cell Death Discov.2015 Jul 27;1:15009. |
 GSK′963A protects mice from TNF+zVAD-induced hypothermia. (a) Pharmacokinetic profile of GSK′963A dosed i.p. at 10 mg/kg in C57BL/6 mice. The data represent the combined results of the three independent animals. (b) Modeling of predicted % inhibition against RIP1 using the observed pharmacokinetic profile of GSK′963 in conjunction with the potency in inhibiting TNF+zVAD necroptosis in mouse L929 cells.Cell Death Discov.2015 Jul 27;1:15009. |
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