选择性VEGFR-2抑制剂的设计、合成及生物活性研究

The receptor tyrosine kinase vascular endothelial growth factor receptor-2 (VEGFR-2) is an important validated target. The VEGF-mediated VEGFR-2 signaling plays a vital role in tumor angiogenesis; over-activation of VEGFR-2 is closely related to growth, metastasis and poor prognosis in the majority of solid tumors. In this project, we would like to design and synthesis selective VEGFR-2 inhibitors for unmet medical needs. First, based on the binding mode of VEGFR-2 and its inhibitor, an approach combining traditional medicinal chemistry and modern drug design techniques will be applied to design new VEGFR-2 inhibitors. Then, the compounds will be synthesized either by employing target-oriented synthetic strategy or by other high efficient synthetic methods. The new compounds will be evaluated for their bioactivities at molecular, cellular and animal levels; the compounds which are active in animal models will be further evaluated on their druggability, such as their pharmacokinetic properties and toxicity profiles. Finally, the privileged molecules will be selected to explore their mechanism of action. In our previous work, we have designed and synthesized 131 derivatives with various scaffolds, some of which showed high potency both in vitro and in vivo. The representative compound DW10139 showed excellent in vitro and in vivo activities. Notably, DW10139 displayed favorable pharmacokinetic profile and tolerable safety property. Therefore, continuation of this project would lead to development of new molecular-targeted anticancer agents with better therapeutic profiles.

酪氨酸激酶血管内皮生长 因子（VEGFR-2 ）是抗肿瘤药物的重要靶点，VEGF所介导的VEGFR-2信号通路在肿瘤血管新生中起重要作用，VEGFR-2的过度激活与肿瘤的生长、转移及预后密切相关。根据VEGFR-2 和其抑制剂的结合模式，结合经典药物设计和现代药物设计方法，设计结构新颖的VEGFR-2抑制剂。采用定向合成和及其它高效化合物制备技术，合成设计的衍生物。采用分子、细胞和动物水平对合成的衍生物进行活性评价。对动物水平有效的化合物进行包括初步药代和毒理的成药性评价。最后对成药性好的衍生物进行作用机制研究，为VEGFR-2抑制剂的研发奠定基础。在前期工作中，我们已设计合成131个结构新颖的化合物，发现了一些高活性高选择性的VEGFR-2抑制剂，其中DW10139在体内外均显示良好的抗肿瘤作用，并具有良好的药代和安评性质。因此，继续开展本项目研究，将有望开发更安全高效的靶点抗肿瘤药物。

酪氨酸激酶血管内皮生长 因子（VEGFR-2 ）是抗肿瘤药物的重要靶点，VEGF所介导的VEG FR-2信号通路在肿瘤血管新生中起重要作用，VEGFR-2的过度激活与肿瘤的生长、转移及预后 密切相关。根据VEGFR-2 和其抑制剂的结合模式，结合经典药物设计和现代药物设计方法，设 计结构新颖的VEGFR-2抑制剂。采用定向合成和及其它高效化合物制备技术，合成设计的衍生 物。采用分子、细胞和动物水平对合成的衍生物进行活性评价。对动物水平有效的化合物进行 包括初步药代和毒理的成药性评价。最后对成药性好的衍生物进行作用机制研究，为VEGFR-2 抑制剂的研发奠定基础。在前期工作中，我们已设计合成131个结构新颖的化合物，发现了一 些高活性高选择性的VEGFR-2抑制剂，其中DW10139在体内外均显示良好的抗肿瘤作用，并具有 良好的药代和安评性质。因此，继续开展本项目研究，将有望开发更安全高效的靶点抗肿瘤药 物。