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 IC 50 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.