New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs |
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Authors: | Yuanyuan Shan Binghe Wang Jie Zhang |
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Affiliation: | 1. Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China;2. Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA;3. School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, ChinaContract grant sponsor: National Natural Science Foundation of China;4. Contract grant number: 81573285. |
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Abstract: | Pathological angiogenesis plays a crucial role in malignant neoplasia. Vascular normalization has been confirmed as a promising strategy to promote chemotherapy efficacy. However, compensatory activation of alternative angiogenic receptor tyrosine kinases (RTKs) reduces vascular normalization and induces resistance. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat with single‐target agents. Accordingly, it has been proposed that multiplex inhibition of RTKs could enhance treatment efficacy and overcome resistance on the basis of the vascular normalization concept. Meanwhile, it is feasible to develop multiplex inhibitors against VEGFR‐2/Tie‐2/EphB4 because of their highly conserved ATP‐binding pockets. These inhibitors possess the properties of not only stabilizing the vascular normalization “time window” but also preventing the occurrence of resistance. This novel strategy has yielded promising results in the discovery of antiangiogenic agents. This review highlights the recent progress on the development of such angiogenesis inhibitors. |
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Keywords: | antiangiogenic effect compensatory activation multiplex inhibitors receptor tyrosine kinase vascular normalization |
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