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.