Development of Second-Generation VEGFR Tyrosine Kinase Inhibitors: Current Status |
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Authors: | Pankaj Bhargava Murray O Robinson |
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Institution: | (1) AVEO Pharmaceuticals, Inc., 75 Sidney Street, 4th floor, Cambridge, MA 02139, USA |
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Abstract: | The vascular endothelial growth factor (VEGF) signaling pathway appears to be the dominant pathway involved in tumor angiogenesis,
providing a rationale for targeting the VEGF receptors (VEGFR-1, -2, and -3) in the treatment of cancers. In particular, VEGF
signaling is thought to be important in renal cell carcinoma (RCC) because of the deregulation of the pathway through nearly
uniform loss of the von Hippel Lindau protein. The tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib are
approved by the US Food and Drug Administration for the treatment of advanced RCC; however, these multitargeted agents inhibit
a wide range of kinase targets in addition to the VEGFRs, resulting in a range of adverse effects unrelated to efficient VEGF
blockade. This article reviews recent advances in the development of the second-generation VEGFR TKIs, including the more
selective VEGFR TKIs tivozanib and axitinib, and focuses on the potential benefits of novel inhibitors with improved potency
and selectivity. |
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