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In vitro: GSK583 possesses comparable binding affinity for RIP3 kinase as demonstrated by an in-house FP binding assay configured similarly to the RIP2 FP assay (RIP2 FP IC50 = 5 nM; RIP3 FP IC50 = 16 nM). Despite this potent biochemical activity against RIP3 kinase, GSK583 shows little or no inhibition of RIP3-dependent necroptotic cell death in a cellular assay up to 10 μM concentration. GSK583 potently and dose dependently inhibits MDP-stimulated tumor necrosis factor-alpha (TNFα) production with an IC50 = 8 nM in primary human monocytes. Following treatment with GSK583 at 1 μM, little inhibition of pro-inflammatory signaling is observed upon activation of Toll-like receptors (TLR2, TLR4, TLR7) or cytokine receptors (IL-1R, TNFR) but complete inhibition is observed upon activation of both NOD1 and NOD2 receptors, which signal in a RIP2-dependent manner. Although GSK583 has excellent kinase selectivity, it does inhibit both the hERG channel and Cyp3A4, which precludes it from further progression as a drug candidate. In vivo: GSK583 has low clearance, moderate volumes of distribution, and moderate oral bioavailability in both rat and mouse. Eventhough GSK583 would not produce a human phamacodynamic response within an acceptable dose range which precludes this molecule from further development as a drug candidate, the oral PK in rat and mouse provides sufficient systemic exposure for use as a preclinical in vivo tool molecule in an acute inflammation challenge mode.
| Cell Experiment | |
|---|---|
| Cell lines | primary human monocytes |
| Preparation method | To assess cellular selectivity, monocytes are pretreated with inhibitor for 30 min, then stimulated for 6 h with ligands which selectively agonize NLRs NOD1, NOD2; Toll-like receptors TLR, TLR4, TLR7, or cytokine receptors IL-1R, TNFR. Release of pro-inflammatory cytokines, either TNFα (NOD2, TLR2, TLR4, IL1R) or IL-8 (NOD1, TLR7, TNFR), is measured by immunoassay. Percent inhibition and/or IC50 values are calculated. |
| Concentrations | 1 μM |
| Incubation time | 30 min |
| Animal Experiment | |
|---|---|
| Animal models | C57BL/6 mice |
| Formulation | |
| Dosages | 0.1, 1, 10 and 100 mg/kg |
| Administration | oral administration |
| Molecular Weight | 398.45 |
| Formula | C20H19FN4O2S |
| CAS Number | 1346547-00-9 |
| Solubility (25°C) | DMSO 80 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Related RIPK Products |
|---|
| Necrostatin-1
Necrostatin-1 (NEC-1) is a potent inhibitor of necroptosis, with an EC50 of 490 nM in Jurkat cells. Necrostin-1 is the first identified RIPK1 inhibitor, EC50=182 nM, that reduces inflammation and inhibits colitis associated tumorigenesis. Necrostatin-1 (Nec-1) is also an inhibitor of IDO. |
| GSK481
GSK481 is a highly effective, selective and specific RIPK1 inhibitor with an IC50 value of 1.3 nM, which can inhibit the phosphorylation of Ser166 in wild-type human RIPK1 (IC50 value of 2.8 nM). The IC50 value of GSK481 against U937 cells was 10 nM. |
| Necrostatin-5
Necrostatin-5 is an inhibitor of necroptosis (non-apoptotic cell death pathway) by indirect inhibition of RIP1 kinase, with an EC50 value of 0.24 µM. |
| WEHI-345
WEHI-345 is a potent and selective RIPK2 inhibitor with IC50 of 0.13 μM. WEHI-345 delays RIPK2 ubiquitylation and NF-κB activation on oligomerization domain (NOD) stimulation. |
| GSK872
GSK872 is a receptor interacting protein kinase-3 (RIP3) inhibitor, which inhibits kinase activity with an IC50 of 1.3 nM. |
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