血管内皮生长因子VEGF是一种多功能血管生长因子，对肿瘤发展至关重要。降低细胞中VEGF含量是有效的抗肿瘤药物设计策略。我们前期研究发现小分子化合物可作用于癌基因调控区的核酸二级结构(G-四链体，G4)及相关转录因子，有效地调控基因转录水平。在人VEGF基因mRNA的非翻译区，存在可形成G4的富G序列，该结构的形成可触发VEGF的翻译起始过程；而该区域内G4与翻译因子eIF4A的结合也可触发翻译起始过程。我们发现，一类新的喹唑啉衍生物能特异性地干扰VEGF mRNA内G4的形成，明显抑制该基因的翻译，显示出了良好的抗肿瘤活性。本课题提出基于干预VEGF翻译调控过程的药物设计策略，拟分别以VEGF mRNA内G4及G4/eIF4A复合物为靶标，设计合成新的小分子干扰物，通过筛选、评价、靶标确证及抗肿瘤作用研究等工作，发现高活性和选择性的血管生成抑制剂。为发现新型抗肿瘤药物提供理论和实验依据。

Vascular endothelial growth factor (VEGF) is a pluripotent cytokine and angiogenic growth factor that plays crucial roles in embryonic development and tumor progression. Lowing the expression of VEGF in tumor cells is proved to be an effective strategy for anti-tumor drugs designing. Our previous studies reveal that small molecules can effectively regulate genes’ transcription via interaction with nucleic acid secondary structures locate within oncogenes’ regulation region, such as G-quadruplexes, and transcriptional factors that binding to them. There is a G-quadruplex forming sequence within the 5’-untranslated region (5’-UTR) of the human VEGF gene. This G-quadruplex is involved in the initiation of VEGF’s translation. Specifically, folding and stabilization of this structure in the internal ribosome enter site (IRES) will stimulate the initiation; on the other hand, recognition and binding of a translation factor eIF4A to the 5’-UTR can recruit the ribosome 40s subunit and thus also initiate the translation process. We found a novel quinazoline derivative could specifically interfere the formation of a G-quadruplex in the IRES region of VEGF’s mRNA, and down-regulate the translation. This compound could also exhibit antitumor activity on MCF-7 xenograft animals. Basing on these findings, we proposed a new drug design strategy for interfering the translational regulation of VEGF gene. We are going to design and synthesize novel small molecular interferers targeting te G-quadruplex in VEGF’s mRNA, or targeting the G-quadruplex-eIF4A complex. We will also plan to apply a panel of in vitro and in vivo experiments to screen and evaluate activities of these novel compounds, to identify their cellular target, and to test their anti-tumor activities. Upon these studies, novel angiogenesis inhibitors with high activity and selectivity will be found.