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

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

Author information

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

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