GSK583

Catalog No.S8261

GSK583 Chemical Structure

Molecular Weight(MW): 398.45

GSK583 is a highly potent and selective inhibitor of RIP2 kinase with an IC50 of 5 nM.

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Biological Activity

Description GSK583 is a highly potent and selective inhibitor of RIP2 kinase with an IC50 of 5 nM.
Targets
RIP2 [1]
(Cell-free assay)
RIP3 [1]
(Cell-free assay)
5 nM 16 nM
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[1].

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 model[1].

Protocol

Cell Research:

[1]

+ Expand
  • Cell lines: primary human monocytes
  • Concentrations: 1 μM
  • Incubation Time: 30 min
  • 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.


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: C57BL/6 mice
  • Formulation: --
  • Dosages: 0.1, 1, 10 and 100 mg/kg
  • Administration: oral administration
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 79 mg/mL (198.26 mM)
Ethanol 28 mg/mL (70.27 mM)
Water Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 398.45
Formula

C20H19FN4O2S

CAS No. 1346547-00-9
Storage powder
in solvent
Synonyms N/A

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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID