LSD1和VEGFs在多种恶性肿瘤中过度表达并异常激活，抑制其活性或下调其表达量可抑制肿瘤的生长、侵袭和转移，是目前抗肿瘤药物研发的热点靶标。LSD1和VEGFs之间相互关联，同时抑制LSD1和VEGFs活性具有协同抗肿瘤效应，是发展肿瘤表观遗传学治疗的新策略。在前期工作中，本课题组已经发现以嘧啶为骨架的LSD1抑制剂可有效的抑制肿瘤的生长、侵袭和转移。在此基础上，借助计算机辅助设计，本项目组设计合成了一类兼具LSD1/VEGFs抑制剂特征的嘧啶衍生物，部分化合物显示出较好的体外抗肿瘤活性。首次发现通过提高小分子与FAD结构的相似性可以提高小分子对LSD1的抑制活性，为LSD1抑制剂的构建提供了新的研究思路。我们期望通过对LSD1、VEGFs抑制活性和体内外抗肿瘤活性评价，筛选出高活性LSD1/VEGFs双靶点抑制剂，初步探索其抗肿瘤作用机制，为研发新型抗肿瘤药物奠定基础。

LSD1 and VEGFs are overexpressed in many human cancers, resulting in aberrant silencing of tumor suppressor genes, downregulation of their expression or inhibition of their activity can prevent cancer growth, migration and invasion. LSD1 and VEGFs have been validated as potential target for the discovery of antitumor agents. Moreover, there are intimate functional cross-talks between the LSD1 and VEGFs. LSD1 cooperates with VEGFs to participate in a multistep process allowing the transition from an active to a repressed state. Simultaneous.inhibition of LSD1 and VEGFs exhibits cooperation and synergy in regulating gene expression and growth inhibition, and represent a promising and novel approach for epigenetic therapy of cancers. In previous work, we have designed, synthesized and identified a novel series of pyridimine-thiourea hybrids, as potent LSD1 inhibitors to modulate cancer cell growth, migration and invasion in vitro and in vivo orally. On the basis of this work, novel compounds with LSD1/VEGFs dual inhibition activities were creatively designed and synthesized, preliminary bioactivity evaluation results showed that some compounds exhibited good anticancer in vitro. For the first time, we found that raising the similarity of structure between small molecule and FAD can improve their LSD1 inhibitory activity, which provides a new theoretical way for optimized design of LSD1 inhibitors. The bioactivity of these new compounds will be evaluated by experiments of LSD1/VEGFs inhibition and antitumor effects in vitro and vivo. The antineoplastic molecular mechanism will be preliminarily explored, including expression of some key proteins and genes related to LSD1/VEGFs signaling pathways. The complement of the present proposal will help us to develop LSD1/VEGFs dual inhibitors as novel anticancer drugs.