TEAD-YAP蛋白相互作用小分子抑制剂的开发及其活性研究

利用生物学方法，竞争性阻断肿瘤细胞内的TEAD/YAP相互作用，能够抑制TEAD介导的基因转录，表现出抗肿瘤活性，是药物研发的热点之一。我们计划通过基于结构的药物设计、合成和优化，获得能够抑制TEAD/YAP相互作用的高活性小分子抑制剂。在基础上，系统优化高活性抑制剂对于TEAD1-4四个亚型选择性、对于其它蛋白相互作用的选择性、以及在动物体内的药代动力学性质，获得具有优异选择性和DMPK-Tox活性的先导化合物。深入研究先导化合物是否阻断细胞内的TEAD/YAP相互作用，其分子水平活性与细胞水平功能是否具有剂量依赖性和相关性，其细胞内的生物学功能是否与现有生物学手段干预后的预期效果一致？最后，阐明TEAD/YAP相互作用高活性、高选择性先导化合物在动物模型内的抗肿瘤药效和药理机制。

Competitive inhibition of TEAD/YAP protein-protein interactions in cancer cells using biological methods resulted in inhibition of TEAD mediated gene transcriptions and had tumor suppressive effects, which is one of the hot areas for drug discovery research. We plan to structure-based design, synthesize, and optimize a series of potent and selective small-molecule inhibitors of TEAD/YAP interactions. Based on these inhibitors, we will systematically study their selectivities among TEAD1-4 and against other protein-protein interactions, and pharmacokinetic properties in animal models in order to obtain selective lead compounds with good DMPK-Tox profile. In addition, whether these lead inhibitors block cellular TEAD/YAP interactions will be investigated. The correlations between the biochemical activities and cellular functions of these lead inhibitors will be examined in a dose-dependent manner. Whether the cellular functions of these lead inhibitors are in consistence with the phenotypes caused by interventions using reported biological methods will also be studied. Finally, the pharmacodynamics and antitumor efficacies of potent and selective lead inhibitors of TEAD/YAP interactions will be carefully evaluated in animal models.