生物活性

• 靶点	MEK IC50:0.33nM

• 描述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.. PD0325901 is a MEK1/2 with IC50 value of 0.33nM^[1]. PD0325901 showed more potency to cell lines harboring BRAF-mutation , including SKMEL28, SKMEL3, SKMEL19, SKMEL1, MALME3M, Colo205 and DU4475, with IC50 values below 10nM, compared with RAS/BRAF-WT cells with IC50>100nM. Meanwhile, dose-dependent decreased p-ERK and Cyclin D1 by PD0325901 can also be observed in these BRAF-mutant cells at concentration>10nM. These suggested that the BRAF mutation may confer the preferential sensitivity of cell lines to MEK inhibition by PD0325901. Consistent with the cellular studies, oral administration with PD0325901 suppressed the tumor growth in mice xenograft SKMEL28 harboring BRAF-V600E mutation at both dose of 5mg/kg and 25mg/kg, accompanied with decrease of p-ERK, Cyclin D1, RB and increased p27. In contrast, treatment with PD0325901 suppressed tumor growth in SKMEL31 (RAS/RAF-WT) xenografts only at high dose (25mg/kg) or even showed no effect in BT-474 (RAS/RAF-WT) xenografts at both dose, regardless the decreased p-ERK by PD0325901^[2]. Also it is found that PD0325901 can enhance generation of iPSCs^[3].
• 作用机制PD0325901 is a derivative of CI-1040, which is a non-competitive inhibitor of MEK1/2.^[2]

• 动物研究
  剂量	Pig: 0.79 mg/kg[4] (p.o.) Mice: 0.5 mg/kg, 1 mg/kg[5] (i.p.), 1.5 mg/kg - 10 mg/kg[6] (p.o.), 25 mg/kg[7] (p.o.) Rat: 10 mg/kg - 100 mg/kg[8] (i.v., p.o.)
  给药途径	p.o., i.p., i.v.
  动物药代数据	Animal Rats[8] Dose 30 mg/kg (i.v. or p.o.) Administration i.v. p.o. Cmax 129 µg/ml (i.v.) 16.9 µg/ml (p.o.) Tmax 1 h (p.o.) AUC0→24h 148 µg·h/ml (i.v..) 82.7 µg·h/ml (p.o.)