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| 10mg |
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| 25mg |
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| 50mg |
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Purity: ≥98%
GSK'547 (GSK547; GSK-547) is a novel, potent and highly selective RIP1 (receptor-interacting serine/threonine protein kinase 1) inhibitor with immunomodulatory properties. Compared to GSK'963, it exhibits a 400-fold increase in mouse pharmacokinetic oral exposure. In a STAT1-dependent manner, RIP1 targeting reprogrammed TAMs (tumor-associated macrophages) toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype. Tumor immunity was produced in mice and organotypic models of human PDA by RIP1 inhibition in TAMs, which led to cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype. Immunotherapies based on PD1 and inducible co-stimulators and RIP1 targeting worked well together. RIP1's tumor-promoting effects were not dependent on RIP3 co-association. Our research as a whole characterizes RIP1 as a checkpoint kinase controlling tumor immunity.
| Targets |
RIPK1
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|---|---|
| ln Vitro |
GSK'547 (RIP1i) treatment in vitro directs the programming of bone marrow-derived macrophages (BMDM) toward an immunogenic phenotype, upregulating MHC-II, TNFa, and IFNg, while concomitantly reducing CD206, IL-10, and TGFb expression. Furthermore, STAT1 signaling is upregulated by RIP1i in BMDM, which is linked to M1 programming, but STAT3, STAT5, and STAT6 signaling are downregulated, which is connected to M2-like macrophage differentiation. The ability of macrophages treated with RIP1i to capture antigen is also improved[1].
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| ln Vivo |
GSK'547 (RIP1i) administration in mouse chow results in in vivo steady-state concentrations over the L929 IC90 over a 24-hour period. Over the course of a 6-week treatment regimen, high serum concentrations of RIP1i are maintained. Without obvious pathology, RIP1i therapy is well tolerated. In comparison to mice treated with controls or Nec-1s, those given RIP1i have less tumor burden and longer survival after being exposed to orthotopic PDA (pancreatic ductal adenocarcinoma) tumor cells derived from KPC mice. Aside from new tumors, RIP1i also guards against liver metastases[1].
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| Cell Assay |
For 30 minutes, RIP1i is pretreated with cells in a variety of doses. 24 hours later, cellular ATP levels are used to assess induced cell death.
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| References |
| Molecular Formula |
C20H18F2N6O
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|---|---|
| Molecular Weight |
396.3933
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| Exact Mass |
396.15
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| Elemental Analysis |
C, 60.60; H, 4.58; F, 9.59; N, 21.20; O, 4.04
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| CAS # |
2226735-55-1
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| Related CAS # |
(Rac)-GSK547
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| Appearance |
Solid powder
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| SMILES |
C1CN(CCC1C(=O)N2[C@@H](CC=N2)C3=CC(=CC(=C3)F)F)C4=NC=NC(=C4)C#N
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| InChi Key |
SJVGFKBLUYAEOK-SFHVURJKSA-N
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| InChi Code |
InChI=1S/C20H18F2N6O/c21-15-7-14(8-16(22)9-15)18-1-4-26-28(18)20(29)13-2-5-27(6-3-13)19-10-17(11-23)24-12-25-19/h4,7-10,12-13,18H,1-3,5-6H2/t18-/m0/s1
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| Chemical Name |
6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile
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| Synonyms |
GSK'547; GSK-547; GSK 547; GSK547; RIP1i
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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) |
DMSO: 29~250 mg/mL (73.2~630.69 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.31 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
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: ≥ 2.08 mg/mL (5.25 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.25 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. Solubility in Formulation 4: (saturation unknown) in (add these co-solvents sequentially from left to right, and one by one), |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5228 mL | 12.6138 mL | 25.2277 mL | |
| 5 mM | 0.5046 mL | 2.5228 mL | 5.0455 mL | |
| 10 mM | 0.2523 mL | 1.2614 mL | 2.5228 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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