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

Yongcong Lv; Mengyuan Li; Ting Liu; Linjiang Tong; Ting Peng; Lixin Wei; Jian Ding; Hua Xie; Wenhu Duan

doi:10.1021/ml5000417

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

ACS Med Chem Lett. 2014 Feb 24;5(5):592-7. doi: 10.1021/ml5000417. eCollection 2014 May 8.

Authors

Yongcong Lv¹, Mengyuan Li², Ting Liu³, Linjiang Tong⁴, Ting Peng⁴, Lixin Wei⁵, Jian Ding⁴, Hua Xie⁴, Wenhu Duan¹

Affiliations

¹ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China.
² Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China ; Northwest Institute of Plateau Biology, Chinese Academy of Sciences , 23 Xinning Road, Qinghai 81008, China.
³ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China ; Medical College of Nanchang University , 461 Bayi Road, Nanchang, Jiangxi 330066, China.
⁴ Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, China.
⁵ Northwest Institute of Plateau Biology, Chinese Academy of Sciences , 23 Xinning Road, Qinghai 81008, China.

Abstract

Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of a new series of naphthamides as potent inhibitors of VEGFR-2. Among these compounds, 14c exhibited high VEGFR-2 inhibitory potency in both enzymatic and HUVEC cellular proliferation assays, with IC50 values of 1.5 and 0.9 nM, respectively. 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 at nanomolar level. Overall, 14c might be a promising candidate for the treatment of cancer.

Keywords: Angiogenesis; HUVEC; VEGFR-2; inhibitor; naphthamide.