Structure-Based Discovery of Novel, Highly Potent VEGFR2 Inhibitors with a Naphthalene Scaffold against a Broad Range of Solid Tumors

Vascular
endothelial growth factor receptors (VEGFRs) represent
pivotal targets in cancer therapy, and developing highly potent VEGFR2
inhibitors remains a prominent research focus. Herein, leveraging
structure-based rational design strategies involving scaffold hopping
and substitution site variation, multiple series of novel naphthalene-scaffolded
VEGFR2 inhibitors were synthesized and systematically evaluated. A
representative compound, E20, was demonstrated as a multitargeted
tyrosine kinase inhibitor exhibiting subnanomolar IC50 value
against VEGFR2 and broad-spectrum antiproliferative potency in vitro, which significantly outperformed lenvatinib. Mechanistically, E20 potently suppressed VEGFR2 and downstream AKT/ERK phosphorylation,
while inhibiting HUVEC proliferation, tube formation, and migration.
Notably, oral administration of E20 remarkably inhibited
hepatocellular, lung, renal, and thyroid tumor growth in vivo with tumor growth inhibition rates exceeding 90%, far superior to
those of lenvatinib. Moreover, E20 showed favorable pharmacokinetics,
improved tolerability, and a wider therapeutic window than lenvatinib.
Collectively, these results validate E20 as a promising
preclinical candidate for treating diverse solid tumors.