Room temperature shipping(Stability testing shows this product can be shipped without any cooling measures.)
Preparing Stock Solutions
1 mg
5 mg
10 mg
1 mM
2.5097 mL
12.5486 mL
25.0973 mL
5 mM
0.5019 mL
2.5097 mL
5.0195 mL
10 mM
0.2510 mL
1.2549 mL
2.5097 mL
50 mM
0.0502 mL
0.2510 mL
0.5019 mL
Description
GSK583 is a highly potent and selective inhibitor of with IC50 of 5 nM. GSK583 also inhibits both and production with IC50 of ~200 nM in explant cultures.
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 model.
