基于结构的多靶标甲羟戊酸途径抑制剂的设计、合成与抗肿瘤活性研究

Mevalonate pathway (MP), a classical therapeutic approach for the treatment and prevention of cardiovascular disease associated with high cholesterol, is closely related to the occurrence and development of cancer. Recently, the antitumor activity and mechanism of MP inhibitors is among the research hot-spots, suggesting the discovery of new MP inhibitors an urgent need for anticancer drug development. In our previous study, a class of novel MP inhibitors were identified from green tea, which showed potent inhibition to three targets on MP - MVK, MDD, and FPPS. Through molecular dynamics simulation, the inhibitors exhibit similar three-dimensional conformation complementary to the binding pockets of all three targets. We herein extracted the spatial pharmacophore feature of such inhibitors and proposed the multi-target mechanism of action. Based on the proposed multi-target active conformation, this project aims to discover novel multi-target MP inhibitors combining structure-based, fragment-based design, synthesis, and MP inhibition assay. The lead compounds are further evaluated for in vitro and in vivo anti-tumor activity. By summarizing structure-activity relationship (SAR), binding mode, and privileged scaffolds or fragments, thereof, this project provides both compound basis and theoretical guidance for the development of novel anticancer drugs with higher potency, less side effect and broader spectrum.

甲羟戊酸途径（Mevalonate pathway，MP）是治疗和预防高血脂相关的心血管疾病的经典治疗途径，与癌症的发生和发展也密切相关。MP抑制剂的抗肿瘤活性与机制是当前的研究热点，发现新型MP抑制剂符合抗肿瘤药物开发的迫切需求。在前期研究中，我们从绿茶的主要成份中发现了一类新型MP抑制剂，可以同时抑制MP上的三个靶标—MVK、MDD、FPPS。通过分子动力学模拟，发现该类抑制剂表现出与这三个靶标互补的相似空间三维构象，进而总结并提出了这类多靶标MP抑制剂的空间药效结构特征和多靶标作用机制。本项目在前期研究的绿茶多酚类抑制剂多靶标活性构象的基础上，结合基于结构和基于片段的理性药物设计方法，设计合成新型多靶标MP抑制剂并进行抗肿瘤活性和机制研究，发现先导化合物。通过总结构效关系、结合模式和优势骨架或片段，为开发副作用更小、活性更强、作用谱更广的新型抗肿瘤药物提供物质基础和理论指导。

甲羟戊酸途径（Mevalonate pathway，MP）是治疗和预防高血脂相关的心血管疾病的经典治疗途径，与癌症的发生和发展也密切相关。MP抑制剂的抗肿瘤活性与机制是当前的研究热点，发现新型MP抑制剂符合抗肿瘤药物开发的迫切需求。在前期研究中，我们从绿茶的主要成份中发现了一类新型MP抑制剂，可以同时抑制MP上的三个靶标—MVK、MDD、FPPS。通过分子动力学模拟，发现该类抑制剂表现出与这三个靶标互补的相似空间三维构象，进而总结并提出了这类多靶标MP抑制剂的空间药效结构特征和多靶标作用机制。本项目在前期研究的绿茶多酚类抑制剂多靶标活性构象（空间药效结构特征）的基础上，采用基于结构和基于片段的理性药物设计方法，搭建了MP抑制剂的结构数据库和逆合成片段库，设计合成了新型多靶标MP抑制剂并进行了抗肿瘤活性研究，发现了全新骨架的先导化合物。通过总结构效关系、结合模式和优势骨架，为开发副作用更小、活性更强、作用谱更广的新型抗肿瘤药物提供了物质基础和理论指导，有显著的科学意义、应用前景和商业价值。