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GSK583 RIP kinase inhibitor

Cat.No.S8261

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

Chemical Structure

Molecular Weight: 398.45

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Quality Control

Batch: S826101 DMSO]79 mg/mL]false]Ethanol]28 mg/mL]false]Water]Insoluble]false Purity: 99.75%
99.75

Chemical Information, Storage & Stability

Molecular Weight 398.45 Formula

C20H19FN4O2S

 Storage (From the date of receipt)
CAS No. 1346547-00-9 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CC(C)(C)S(=O)(=O)C1=CC2=C(C=CN=C2C=C1)NC3=NNC4=C3C=C(C=C4)F

Solubility

In vitro
Batch:

DMSO : 79 mg/mL (198.26 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 28 mg/mL

Water : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Mechanism of Action

Targets/IC50/Ki
RIP2 [1]
(Cell-free assay)
5 nM
RIP3 [1]
(Cell-free assay)
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, this compound shows little or no inhibition of RIP3-dependent necroptotic cell death in a cellular assay up to 10 μM concentration. It 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 this chemical 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 it has excellent kinase selectivity, this compound 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 this compound 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].
References

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