GSK583

Catalog No.S8261 Batch:S826101

Technical Data

Formula	C₂₀H₁₉FN₄O₂S
Molecular Weight	398.45	CAS No.	1346547-00-9
Solubility (25°C)*	In vitro	DMSO	79 mg/mL (198.26 mM)
		Ethanol	28 mg/mL (70.27 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or 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. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

GSK583 is a highly potent and selective inhibitor of RIP2 kinase with IC50 of 5 nM. GSK583 also inhibits both TNF-α and IL-6 production with IC50 of ~200 nM in explant cultures.

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 (from reference)

Cell Assay:^{^[1]}	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.
Animal Study:^{^[1]}	Animal Models C57BL/6 mice Dosages 0.1, 1, 10 and 100 mg/kg Administration oral administration

Cell Assay:^{^[1]}

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.

Animal Study:^{^[1]}

Animal Models
C57BL/6 mice
Dosages
0.1, 1, 10 and 100 mg/kg
Administration
oral administration

References

[1] Haile PA, et al. J Med Chem. 2016, 59(10):4867-80.

Selleck's GSK583 has been cited by 2 publications

Deletion of Glutathione S-Transferase Omega 1 Activates Type I Interferon Genes and Downregulates Tissue Factor [ Cancer Res, 2020, canres.530.2020]	PubMed: 32571799
NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice [ J Neuroinflammation, 2020, 17(1):364]	PubMed: 33261639

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SHIPPING AND STORAGE
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