The mammalian Raf kinase family consists of A-Raf and B-Raf and c-Raf (or Raf 1). The c-Raf has been proven an upstream activator of mitogen-activated protein kinase (MAPK), which is an important group of mediators transducing signals from cell surface to nucleus under stimuli including cytokines, growth factors, exogenous pressure and mitogens. The RAF was also proven to be an oncogenic gene that was closely associated with tumorigenesis[3]. GW5074 is a potent inhibitor of c-Raf with an IC50 value of 9 nM. Treatment with GW5074 for 24 hours prevents LK-induced apoptosis in medium containing LK. Maximal protection against LK-induced apoptosis is observed at 1 μM. The activity of c-Raf immunoprecipitated from cultures treated with GW5074 in LK medium displayed a marked induction. Dispite its inhibition of c-Raf, treatment of neuronal cultures with GW5074 lea to an increase in the phosphorylation of ERK 1/2 suggesting that GW5074 treatment caused the activation of either A-Raf or B-Raf. Mice administered 3-NP display extensive bilateral striatal lesions. This degeneration is completely prevented by GW5074 when administered at a concentration of 5 mg/kg body weight[4].
作用机制
c-Raf is inhibited by phosphorylation at Ser259 with GW5074[4].
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