A novel synthetic small molecule YF-452 inhibits tumor growth through antiangiogenesis by suppressing VEGF receptor 2 signaling
A novel synthetic small molecule YF-452 inhibits tumor growth through antiangiogenesis by suppressing VEGF receptor 2 signaling
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一种新型合成小分子 YF-452 通过抑制 VEGF 受体 2 信号传导来抗血管生成，从而抑制肿瘤生长。
DOI：
10.1007/s11427-016-0369-6
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发表时间：
2017-02-01
影响因子：
9.1
通讯作者：
Yi, Zhengfang
中科院分区：
文献类型：
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作者：
Liu, Yongrui;He, Yuan;Yi, Zhengfang
肿瘤血管生成的特点是血管形态异常，使肿瘤高度缺氧，对治疗无反应。到目前为止，越来越多的血管生成因子被发现是抗血管生成药物开发的治疗靶点。其中，血管内皮生长因子受体2(VEGFR2)抑制剂在肿瘤治疗中具有很强的抗血管生成活性。因此，通过VEGFR2通路靶向肿瘤血管生成可能为肿瘤的治疗提供一种有效的策略。在本研究中，我们建立了一个备受瞩目的化合物文库，并鉴定了一个新的化合物namedN-(N-pyrrolidylacetyl)-9-(4-bromobenzyl)-1，3，4，9-tetrahydro-β-carboline(YF-452)，它在体外能显著抑制人脐静脉内皮细胞的迁移、侵袭和管状结构的形成，毒性小。大鼠胸主动脉环实验表明，YF-452可明显阻断体内微血管的形成。此外，YF-452还抑制鸡绒毛膜尿囊膜(CAM)和小鼠角膜微袋实验中的血管生成。此外，YF-452还能显著抑制小鼠移植瘤的生长。进一步的分子机制研究表明，YF-452抑制了血管内皮生长因子诱导的VEGFR2激酶及其下游蛋白激酶的磷酸化，包括细胞外信号调节激酶(ERK)、粘着斑激酶(FAK)和Src。这些结果表明，YF-452抑制血管生成，可能是一种潜在的抗血管生成药物用于癌症治疗。
Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound namedN-(N-pyrrolidylacetyl)-9-(4-bromobenzyl)-1,3,4,9-tetrahydro-β-carboline (YF-452), which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells (HUVECs) with little toxicityinvitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation of microvascularexvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane (CAM) and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase (ERK), focal adhesion kinase (FAK) and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.