A cell-permeable pyrimidylpyrrole compound that acts as an active site-targeting, highly potent and selective ERK1/2 inhibitor (KI <2nM against Erk2; [ATP] = 65uM), while inhibiting GSK-3, Aurora A, Cdk2 only at much higher concentrations (KI = 395, 540, and 852nM, respectively) and exhibiting much reduced or little potency toward a panel of more than 130 other kinases (KI ≥1.4uM; IC50 ≥1uM). Shown to effectively inhibit human colon carcinoma HT-29 proliferation (IC50 = 48nM) and restore EGFR inhibitor WZ4002 antiproliferation activity in WZR10 cultures (84% and no inhibition, respectively, by 100nM WZ4002 with or without 1uM Erk Inhibitor VIII co-treatment). Orally available in both mice and rats in vivo.
