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

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

  • J Med Chem. 2026 Apr 9;69(7):8340-8363. doi: 10.1021/acs.jmedchem.5c03743.
Tingting Yang 1 2,  Ting Wei 1,  Shiyang Sun 1,  Bin Xi 2,  Pengli Wei 1,  Changkai Jia 1,  Zhenze Qi 1,  Fan Feng 3,  Meijiao Wei 4,  Yalei Wang 1,  Xu Cai 1,  Zhiyuan Zhao 1,  Bingkun Li 1,  Min Qiao 1,  Yaxin Zou 1,  Zhihui Mu 1,  Xiaofang Lei 1,  Ziyun Zhang 1,  Guanglin Lei 3,  Kai Lv 4,  Zhibing Zheng 1,  Pengyun Li 1,  Song Li 1
Affiliations

Affiliations

  • 1 National Engineering Research Center for the Emergency Drug, Beijing 100039, P. R. China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 3 Department of Clinical Laboratory, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 41858156 DOI: 10.1021/acs.jmedchem.5c03743
Abstract

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.

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