Discovery of 2‑Amino-7-Amide Quinazoline Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Extracellular Signal-Regulated Kinase 1/2

Aberrant activation of the ERK/MAPK pathway is closely associated with various cancers. Directly targeting ERK1/2, the most distal node of this cascade, is not only a rational therapeutic approach for cancers harboring pathway-activating alterations, but also provides a potential solution for overcoming resistance from upstream signaling. Herein, we described the discovery of potent and orally bioavailable ERK1/2 inhibitors featuring 2-amino-7-amide quinazoline skeletons through structure-based drug design. Among them, the optimal compound 23 inhibited ERK1/2 at single-digital nanomolar concentrations with good specificity, and exhibited great potencies in preventing cell growth, migration and invasion, disrupting cell cycle, and inducing cell apoptosis. Further mechanism studies demonstrated that 23 dose-dependently suppressed the phosphorylation of the downstream substrate RSK. Remarkably, 23 exerted favorable ADMET and PK profiles, as well as significant in vivo antitumor efficacy with excellent tolerance. Collectively, this work offers a novel and highly promising candidate targeting ERK1/2 for further drug development.