Abstract
Axitinib is an approved kinase inhibitor for the therapy of advanced metastatic renal cell carcinoma (RCC). It prevents angiogenesis, cellular adhesion, and induces apoptosis of cancer cells. Here, nine axitinib derivatives were designed by replacing the C=C moiety with the N=N group, and the substituted benzene or pyrrole analogs were considered to replace the pyridine ring. Biological activity results showed that most of nascent derivatives exhibited favorable VEGFR-2 kinase inhibitory activities, and TM6, 7, 9, and 11 behaved more potent anti-proliferative activities than axitinib. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.
Highlights
Angiogenesis is a process of new blood vessels sprouting from existing vasculature, which plays a major role in wound healing, tissue repair, and some pathological disorders like tumor growth
A key pro-angiogenic cytokine released by many tumor types is vascular endothelial growth factor (VEGF)
The angiogenic activity of the VEGF family of proteins is mediated by two high affinity receptors, VEGFR-1 and VEGFR-2 located on vascular endothelial cells, with a third, VEGFR-3 which mediates lymphangiogenesis, found on lymphatic vessels, but VEGFR-2 is the predominant VEGF isoform responsible for the majority of downstream effects
Summary
Angiogenesis is a process of new blood vessels sprouting from existing vasculature, which plays a major role in wound healing, tissue repair, and some pathological disorders like tumor growth. Angiogenesis is essential for supplying growing tumors with oxygen, nutrients, and growth factors, removing the waste products of metabolism [1]. Tumors that lack an adequate vasculature become necrotic or apoptotic and do not grow beyond a limited size. A key pro-angiogenic cytokine released by many tumor types is vascular endothelial growth factor (VEGF). The angiogenic activity of the VEGF family of proteins is mediated by two high affinity receptors, VEGFR-1 and VEGFR-2 located on vascular endothelial cells, with a third, VEGFR-3 which mediates lymphangiogenesis, found on lymphatic vessels, but VEGFR-2 is the predominant VEGF isoform responsible for the majority of downstream effects. Inhibition of the VEGF signaling pathway has shown one of the most promising approaches for cancer therapy [2,3]
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