具有抗肿瘤血管生成作用的VEGFR2抑制剂的研究进展

Research advance of VEGFR2 inhibitors as anti-angiogenic agents

肿瘤血管生成是肿瘤生长与转移的重要过程。血管内皮生长因子(vascular endothelial growth factor,VEGF)和它们的受体(VEGFR1,2,3)调控内皮细胞的增殖与迁移,在很多肿瘤内高表达。对VEGFR的抑制已成为许多癌症的有效疗法。VEGFR2在肿瘤血管生成中起重要作用,VEGFR2磷酸化是肿瘤血管生成的重要过程,抑制这个过程是利用VEGF信号通路治疗癌症的主要机理之一。使用抗体和小分子与VEGF结合或者干扰不同的VEGFR结构域可以阻断VEGF信号通路。许多小分子VEGFR2抑制剂得到开发,大部分为多靶点抑制剂,FDA已批准一系列VEGFR2抑制剂上市。本文对已上市及进入临床研究晚期的VEGFR2小分子抑制剂及其活性、临床应用进行了综述,并对它们的构效关系作出了简要分析。发挥多靶点抑制剂的优点,规避其带来的毒副作用,是有希望的研究方向。

Tumorangiogenesis is an important process of tumor growth and metastasis. Vascular endothelial growth factor （VEGF） and their receptors （VEGFR1, 2, 3） regulate the proliferation and migration of endothelial cells and are highly expressed in many tumors. The inhibition of VEGFR has become an effective therapy for many cancers. VEGFR2 plays an important role in tumor angiogenesis. VEGFR2 phosphorylation is a key factor in the mechanism of VEGF signaling pathway and cancer angiogenic process. VEGF signaling pathways can be blocked by antibodies and small molecules binding to VEGF and interfering with different VEGFR domains. Many small molecule VEGFR2 inhibitors, most of which are multi-target inhibitors, have been developed by researchers and approved by FDA. This review reports small molecule VEGFR2 inhibitors launched and in late-phase clinical study, their activities, recent clinical trials and makes a brief analysis of their structure-activity relationship （SAR）. Future research may take advantage of multi-target inhibitors while avoiding their side effects.