ERK Inhibitor VIII

A cell-permeable pyrimidylpyrrole compound that acts as an active site-targeting, highly potent and selective ERK1/2 inhibitor (KI <2 nM against Erk2; [ATP] = 65 µM), while inhibiting GSK-3, Aurora A, Cdk2 only at much higher concentrations (KI = 395, 540, and 852 nM, respectively) and exhibiting much reduced or little potency toward a panel of more than 130 other kinases (KI ≥1.4 µM; IC50 ≥1 µM). Shown to effectively inhibit human colon carcinoma HT-29 proliferation (IC50 = 48 nM) and be orally available in both mice (F = 67%; t1/2 = 4.4 h; Plasma conc. = 488 and 122 ng/mL, respectively, 4 h and 8 h post single 33 mg/kg oral dosage) and rats (F = 65%; t1/2 = 3 h; Plasma conc. = 329 and 267 ng/mL, respectively, 4 h and 8 h post single 10 mg/kg oral dosage) in vivo. Also reported to restore EGFR inhibitor WZ4002 antiproliferation activity in WZR10 cultures (84% and no inhibition, respectively, by 100 nM WZ4002 with or without 1 µM Erk Inhibitor VIII co-treatment).