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.

血管内皮生长因子受体（VEGFRs）是癌症治疗的关键靶点，开发高效能的VEGFR2抑制剂仍是重要的研究热点。本文采用基于结构的合理设计策略，包括骨架跃迁与取代位点变异，合成了多系列新型萘骨架VEGFR2抑制剂并进行系统评价。代表性化合物E20被证实为多靶点酪氨酸激酶抑制剂，对VEGFR2展现出亚纳摩尔级的半数抑制浓度（IC50），且体外广谱抗增殖活性显著优于仑伐替尼。机制研究表明，E20可强效抑制VEGFR2及其下游AKT/ERK磷酸化，同时抑制人脐静脉内皮细胞（HUVEC）的增殖、管形成及迁移能力。值得注意的是，口服给予E20可在体内显著抑制肝细胞癌、肺癌、肾癌及甲状腺癌的肿瘤生长，肿瘤生长抑制率超过90%，其疗效远优于仑伐替尼。此外，与仑伐替尼相比，E20具有更优异的药代动力学特性、更高的耐受性以及更宽的治疗窗口。综上，上述研究结果证实E20是一款极具潜力的临床前候选化合物，可用于治疗多种实体瘤。