ERK1/2 (extracellular-signal-regulated kinases) is only known substrates of the MEK1/2 as well as the essential node in RAS/RAF/MEK/ERK signaling cascade, which can be activated by catalyzing the phosphorylation on T202/Y204 through MEK1/2. SCH772984 is a specific and potent ERK1/2 inhibitor with IC50 value of 4 and 1 nM (measured by in vitro kinase activity). Exposure to SCH772984 at concentration ranging in 30-300nM dose-dependently inhibited the phosphorylation of ERK substrate, p90 ribosomal S6 kinase (RSK), on T359/S363 site, as well as caused the inhibition of phosphorylation of residues in the activation loop of ERK itself at the higher dose (>100 nM). This was further confirmed by comparison with the ATP-competitive ERK inhibitor, VTX-11e. Though both of this two inhibitor inhibited p-RSK at concentration ranging in 0.1-2 μM in BRAFV600E-mutant A375 melanoma cell line, only SCH772984 showed suppression on p-ERK. The cell growth assay studies showed that SCH772984 was efficacious on growth inhibition of RAS- or BRAF- mutant cancer cells, as well as in cells resistant to single-agent BRAF or MEK inhibitor tested. Consistent with this cellular results, intraperitoneal injection with SCH772984 at dose of 12.5, 25 and 50 mg/kg, twice daily for 14 days, efficiently suppressed tumor growth, with obvious p-ERK inhibition, in human LOX BRAF-mutant melanoma xenograft model, while suppression of MiaPaCa KRAS-mutant pancreatic tumor growth can be observed at dose of both 25 and 50 mg/kg in nude mice[1].
作用机制
SCH772984 may inhibit ERK1/2 both through ATP-competition and inducing or stabilizing a conformational state in ERK that prevents activation by MEK.[1]
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