病理性血管生成会导致多种疾病，抗血管生成药物诱导的血管正常化有重要治疗意义；但促血管生成代偿性通路的激活，会缩短血管正常化的"时间窗"并导致耐药性。课题组前期发现的水杨醛肟类VEGFR-2抑制剂BPS-7，对促血管生成的受体酪氨酸激酶EphB4、TIE-2也有选择性抑制并有初步的血管正常化诱导效应。本课题基于血管正常化"时间窗"理论以及VEGFR-2/EphB4/TIE-2可代偿性激活的发现，以BPS-7为新型先导物，分析三种受体活性位点的保守构象并寻找共性结构域；在水杨醛肟基础上采用"Hybridization"和"Mix-n-match"的策略，构建满足共性结构域构象要求的化合物库，通过多水平活性筛选发现同时拮抗三条代偿性通路的多靶标抑制剂，以期实现①稳定血管正常化的"时间窗"；②降低耐药性发生。在抗血管生成的同时促进血管正常化，增强药物转运和敏感性，为新型抗血管生成药物发现奠定基础。

Pathological angiogenesis plays a critical role in numerous diseases. Vascular normalization induced by anti-angiogenesis drugs appears to play an essential role in the intervention for pathological angiogenesis. However, the compensatory activation of pro-angiogenesis factors shortens the vascular normalization "time window" and induces the occurrence of resistance. We have identified a novel biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as potent and selective VEGFR-2 inhibitor through structural optimization of taspine. Fortunately, BPS-7 also displayed selective inhibitory activities against angiogenesis-related EphB4 and TIE-2. Moreover, it has been validated that the three angiogenesis-related RTKs could be compensatory activated by each other as alternative pro-angiogenic pathways. Accordingly, we propose that multiplex inhibition of VEGFR-2, EphB4, and TIE-2 would enhance anti-angiogenesis effect on the basis of vascular normalization concept. Encouraged by previous results, this project will develop multiplex inhibitors of VEGFR-2/EphB4/TIE-2 based on their highly conserved DFG-out conformation. We initiate a medicinal chemistry program to identify the key structural elements required for the kinase inhibition. The design strategies of "hybridization" and "mix-n-match" will be adopted with BPS-7 as lead compound. All the title compounds possess structural diversity with salicylaldoxime as hinge-binding moiety. It is a medicinal chemistry campaign aimed at improving the potency and selectivity profile of BPS-7. In order to evaluate the potency and selectivity of the title compounds, various biological assays will be carried out. This project will identify the first class of multiplex inhibitors of VEGFR-2/EphB4/TIE-2 with a "triplet" inhibition profile. They can not only stabilize the vascular normalization "time window", but also prevent the occurrence of resistance. The normalized vasculature can lead to an improvement in the delivery and efficacy of therapeutic drugs. This project may contribute to the discovery of novel anti-angiogenesis agents for the intervention of pathological angiogenesis-related diseases.