Discovery of Highly Potent, Selective, and Efficacious Small Molecule Inhibitors of ERK1/2

Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (<i>S</i>)-<b>14k</b>, a potent, selective, and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary safety profiles, (<i>S</i>)-<b>14k</b> was selected for further preclinical evaluation