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. GDC-0994 is a selective inhibitor of ERK1/2 with IC50 value of 6.1nM and 3.1nM (measured by enzyme potency), respectively. Cellular study showed that GDC-0994 could inhibit ERK dependent p-RSK with IC50 value of 12nM in PMA-stimulated HepG2 cells[1]. Distinguished with the other published ERK inhibitors, GDC-0994 did not change the level of p-ERK, suggesting the alternative mechanisms of action with respect to feedback signaling of it[2]. The inhibition of p-RSK in these tumors correlating with potency in vitro and in vivo may be the pharmacodynamics biomarker. Oral administration with GDC-0994 once daily for 21 days caused significant tumor growth inhibition by 49%, 57% and 80% at dose of 30, 60 and 100mg/kg in nude mice bearing HCT116 xenograft tumors[1].
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