生物活性

• 靶点

  MEK1 IC50:5nM-2μM

  MEK2 IC50:5nM-2μM

• 描述MEKs, which are members of the MAPKK family, can activate both ERK1 and ERK2 by catalyzing the phosphorylation on T202/Y204. It is found that the tumor growth, like multiple myeloma, and survival, as well as angiogenesis and drug resistance are markedly associated with the MEK/ERK signal transduction pathway. Pimasertib is a potent and selective inhibitor of MEK1/2. As prediction by the inhibition of MEK1/2 kinase activity, incubation with Pimasertib at concentration ranging in 5-2000nM for 1h caused dose-dependent as well as time-dependent, at concentration of 200nM within 72h, decrease of p-ERK1/2 in U266 cells. A further study showed that Pimasertib can targeted multiple myeloma cells in the BMSCs microenvironment specifically through block of MEK/ERK pathway and improved agent. Exposure to Pimasertib at concentration>20nM significantly decreased the secretion of the cytokines induced by adhesion of MM cells to BMSCs, including VEGF and IL-6 in a dose-dependent manner. Treatment with 0.5μM Pimasertib alone over 8h significantly triggered apoptosis, shown as PARP and caspase 3 cleavage in H929 MM cells, as well as increased subG0 and decreased S phase cell population at 0.1μM in both H929 and U266 cells within 72h. Combination of Pimasertib (20nM-20μM) with anti-MM drugs rapamycin (0.1-100nM) for 2 days can augment MM1S cell death. Orally treatment with Pimasertib at dose of both 15mg/kg and 30mg/kg, BID, 5 days per week for 2 weeks, inhibited human MM cell growth in mice bearing H929 MM tumours, accompanied with decreased p-ERK and induced apoptosis. Reduced percentage of CD34+ cells and microvascular density can also be observed in H929 tumours from mice treated with Pimasertib, suggesting the possible inhibitory effect on angiogenesis by Pimasertib in vivo^[1].
• 作用机制Pimasertib is an non-ATP competitive inhibitor of MEK1/2.^[1]

• 动物研究
  剂量	Mice: min = 10 mg/kg[2], max = 30 mg/kg[1]
  给药途径	p.o.