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, <b>E20</b>, was demonstrated as a multitargeted tyrosine kinase inhibitor exhibiting subnanomolar IC₅₀ value against VEGFR2 and broad-spectrum antiproliferative potency <i>in vitro</i>, which significantly outperformed lenvatinib. Mechanistically, <b>E20</b> potently suppressed VEGFR2 and downstream AKT/ERK phosphorylation, while inhibiting HUVEC proliferation, tube formation, and migration. Notably, oral administration of <b>E20</b> remarkably inhibited hepatocellular, lung, renal, and thyroid tumor growth <i>in vivo</i> with tumor growth inhibition rates exceeding 90%, far superior to those of lenvatinib. Moreover, <b>E20</b> showed favorable pharmacokinetics, improved tolerability, and a wider therapeutic window than lenvatinib. Collectively, these results validate <b>E20</b> as a promising preclinical candidate for treating diverse solid tumors.