tcsc0062 PD0325901

PD0325901 is a selective and non ATP-competitive MEK inhibitor with IC₅₀ of 0.33 nM, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2.

IC50 & Target: IC50: 0.33 nM (MEK)

In Vitro: PF0325901 shows higher permeability, and should be able to achieve higher systemic exposures than CI-1040^[1]. PD0325901 is exquisitely specific and highly potent against purified MEK, revealing a K_i^app of 1 nM against activated MEK1 and MEK2. PD0325901 is roughly 500-fold more potent than CI-1040 with respect to its cellular effects on phosphorylation of ERK1 and ERK2, displaying subnanomolar activity. PD0325901 prevents the growth of melanoma cell lines. PD0325901 inhibits the growth of TPC-1 cells and K2 cells with GC₅₀ of 11 nM and 6.3 nM, respectively. PD0325901 significantly prevents the the growth of PTC cells harboring a BRAF mutation at very low concentration (10 nM) and only moderately increases the growth of the PTC cells carrying the RET/PTC1 rearrangement at the same concentration. PD0325901 effectively inhibits the phosphorylation of ERK1/2 in multiple PTC cell lines^[2]. 

In Vivo: PD0325901 (25 mg/kg, p.o.) inhibits phosphorylation of ERK by more than 50% at 24 hours post-dosing. The dose required to produce a 70% incidence of complete tumor responses (C26 model) is 25 mg/kg/day versus 900 mg/kg/day for PD0325901 and CI-1040, respectively. Anticancer activity of PD 0325901 has been demonstrated for a broad spectrum of human tumor xenografts. PD0325901 (20-25 mg/kg/day, p.o.) treatment in mice, shows no tumor growth inoculated with PTC cells bearing a BRAF mutation. For PTC with the RET/PTC1 rearrangement, the average tumor volume of the orthotopic tumor is decreased by 58% as compared with controls. PTC cells carrying a BRAF mutation are more sensitive to PD0325901 than are PTC cells carrying the RET/PTC1 rearrangement^[2].