新型LSD1/VEGFs双靶点抑制剂的设计、合成及抗肿瘤活性评价

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.

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。在项目执行过程中，取得了突破性的研究进展，发现了多个具有进一步优化空间和开发前景的先导化合物，主要成果如下：1）构建了以5-氰基-6苯基嘧啶和缩胺基硫脲为主要骨架的结构多样性小分子化合物库，为基于靶标的药物设计及系统的构效关系研究提供了分子基础；2）首次提出基于FAD结构相似性构筑LSD1抑制剂的设计思路并合成了系列5-氰基-6-苯基嘧啶类衍生物；其中代表性化合物14q可通过竞争性占据FAD与LSD的结合位点抑制LSD1活性并通过抑制EMT过程抑制肿瘤的侵袭和转移。这些发现初步证实通过提高小分子与FAD结构相似性，竞争FAD与LSD1的结合位点可有效增强LSD1的抑制活性设计思路的可行性，为基于LSD1靶标的药物设计提供了新的方向和借鉴；3）首次发现以5-氰基-6-苯基嘧啶为骨架的LSD1抑制剂可有效增强耐药结肠癌细胞SW620/AD300对具有血管生成抑制功能药物紫杉醇的敏感性，且与VEGF介导的肿瘤EMT密切相关。这些发现为MDR发生发展的机制探究提供了新的思路和借鉴；4）在项目执行期间，先后在Acta Pharmaceutica Sinica B、Journal of medicinal chemistry、European Journal of Medicinal Chemistry等国内外药学权威杂志发表与本研究相关的SCI论文18篇，其中第一作者或通讯作者中科院一区论文15篇，2020年APSB读者最喜爱的封面论文一篇；授权国家发明专利6项。