Many factors are involved in tumor angiogenesis, among which the vascular endothelial growth factors (VEGFs) play amajor role. Over activation of vascular endothelial growth factor receptors (VEGFRs), especially VEGFR-2, is closely related to poor prognosis and metastasis in the majority of solidtumor patients. The VEGF-mediated VEGFR-2 signaling promotes several endothelial responses required for the formation of new blood vessels, such as cell proliferation, migration, and survival.

As VEGFR-2 signaling is important in tumor angiogenesis, blocking VEGFR-2 signaling pathway has become an attractive approach for the treatment of cancers. Receptor tyrosine kinase (RTK) inhibitors that target VEGFR-2 have been demonstrated to possess substantial antitumor activity, and generally they are ATP-competitive small molecule inhibitors. In fact, six such inhibitors (sorafenib, sunitinib, pazopanib, axitinib, vandetanib, and regorafenib) targeting VEGFR-2 and/or other kinases have been approved for the treatment of cancers.

Using linifanib (ABT-869) as a lead compound, Prof. DUAN Wenhu and DING Jian groups in Shanghai Materia Medica, Chinese Academy of Sciences design and synthesis a new series of naphthamides as potent VEGFR-2 inhibitors.Privileged compound 14c exhibited high potency in both enzymatic and cellular assays.Kinase selectivity profiling revealed that 14c was a multitargeted inhibitor, and it also exhibited good potency against VEGFR-1, PDGFR-β, and RET. Furthermore, 14c effectively blocked tube formation of HUVEC atnanomolar level.

This work has been published on ACS Medicinal Chemistry Letters（YongcongLv, Mengyuan Li, Ting Liu, Linjiang Tong, Ting Peng, Lixin Wei, Jian Ding, Hua Xie,* WenhuDuan.* Discovery of a New Series of Naphthamides as Potent VEGFR-2 Kinase Inhibitors. ACS Med. Chem. Lett.,2014,5(5), 592–597.）.

Discovery of a New Series of Naphthamides as Potent VEGFR-2Kinase Inhibitors

（Source: Prof.Duan Wenhu’s Group）