RSK (p90 ribosomal S6 kinase) is a member of the AGC subfamily that is activated by the mitogen-activated protein kinase in response to extracellular agonists. BI-D1870 is a specific inhibitor of RSK isoforms with >500-fold greater selectivity over other AGC kinases. In the kinase assays with 100 μM ATP, BI-D1870 inhibited RSK1 and RSK2 with IC50 values of 10 nM and 20 nM, respectively. When the concentration of ATP decreased to 10 μM, the IC50 values of BI-D1870 was reduced to 5 nM for RSK1 and 10 nM for RSK2. BI-D1870 also inhibited an active mutant of RSK2 lacking the C-terminal kinase catalytic domain with an IC50 of 30 nM. In HEK-293 cells that were incubated with 10 μM BI-D1870 for 15 min prior to the stimulation with 20 ng/ml PMA, the PMA-induced phosphorylation of GSK3α and GSK3β was strongly inhibited compared to non- BI-D1870-treated cells. When HEK-293 cells were pretreated with 10 μM BI-D1870 for 30 min before PMA stimulation, the phosphorylation of LKB1 was inhibited with an IC50 value of approximately 1 μM. In serum-deprived Rat-2 cells that were incubated with BI-D1870 for 30 min, EGF-induced phosphorylation of LKB1 at Ser431 was inhibited with an IC50 of around 1 μM. Incubation of Rat-2 cells with 10 μM BI-D1870 for 30 min led to 50% less phosphorylation of ERK1 and ERK2 compared to the level that was observed immediately followed the EGF stimulation. In experimental autoimmune encephalomyelitis mice, i.p. administration of BI-D1870 (0.5 mg/kg) every other day for 11 days resulted in delayed neural deficit, decreased number of CD4+ T cells that infiltrated into the CNS, and reduced mRNA levels of Ccr6 in Th17 cells.
作用机制
BI-D1870 is a RSK inhibitor derived from dihydropteridinones. BI-D1870 competes with ATP to inhibit the N-terminal AGC kinase domain.
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