PD98059 is a non-ATP competitiveMEK inhibitor with IC50 of 2 μM, specifically inhibits MEK-1-mediated activation of MAPK and does not directly inhibit ERK1 or ERK2.
MEKs, which are members of the MAPKK family, can activate both ERK1 and ERK2 by catalyzing the phosphorylation on T202/Y204. Also MEK itself can be phosphorylated and activated through Ras when the upstream signaling is activated by extracellular stimuli, including growth factors, hormones etc.. PD98059 is MEK1/2-specific inhibitor with IC50=~10uM (measured by phosphorylation level of MAPK-KA catalyzed by GST-MEK1) with no effect on ERK. Pre-incubation of PD98059 can inhibit PDGF-stimulated tyrosine phosphorylation of MAPK while preventing thymidine incorporation with an IC50 of 7 uM in 3T3 cells. PD98059 did not show significant inhibitory activity on Raf kinase, cAMP-dependent kinase, protein kinase C, v-Src, EGF receptor kinase, insulin receptor kinase, PDGFreceptor kinase, and PI3Ks, which shows the high selectivity of it [1]. PD98059 is the first generation small molecule inhibitors of MEK1/2. PD98059 does not interfere with Raf access to MEK1/2 for it did not affect serum-induced MEK1/2 phosphorylation [2].
作用机制
PD 098059 does not complete for ATP binding or MAPK binding to MEK and most likely inhibits through an allosteric mechanism.[1]
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