基于MDM2/HDAC双靶抑制策略的抗肿瘤先导化合物发现和优化

p53-MDM2 and HDAC are promising targets for the development of novel antitumor drugs. However, their single-targeting inhibitors have several drawbacks, such as limited efficacy and toxic side effects. In contrast, multi-targeting drugs have many advantages in cancer therapy. Based on the biological functions of MDM2/HDAC and the synergism of their inhibitors in antitumor therapy, we proposed for the first time that designing a single-molecule inhibitor simultaneously targeting HDAC and MDM2 could be an effective strategy in cancer therapy. According to the binding modes of known HDAC and MDM2 inhibitors, the first MDM2/HDAC dual inhibitors were designed and synthesized using the pharmacophore fusion strategy. Preliminary structural optimization and biological activity studies confirmed the lead compound MHA4 showed excellent dual-targeting inhibitory activity as well as antitumor potency, which preliminarily validated the scientific hypothesis at the molecular, cellular and animal level. Inspired by these results, this project will focus on the elucidation of the mechanism of action, improving the balanced dual targets inhibitory activities and drug-like properties of MHA4. As a result, this project aims to discover highly active and drug-like antitumor candidate and provides a basis for the development of novel multi-targeting antitumor agents.

p53-MDM2和HDAC是当前抗肿瘤新药研发的热门靶点，但其单一抑制剂存在疗效有限、毒副作用大等缺陷。鉴于多靶点药物在肿瘤治疗中的诸多优势，本项目基于MDM2/HDAC在生物学功能及其抑制剂在抗肿瘤药效上的协同效应，首次提出了设计MDM2/HDAC双靶抑制剂作为抗肿瘤治疗的新策略。结合理论和研究基础，本课题根据MDM2和HDAC抑制剂结合模式，利用药效团融合策略设计合成了首个MDM2/HDAC双靶点抑制剂。经初步构效关系和生物活性研究，证实先导化合物MHA4在分子、细胞和动物水平均具有优秀的靶点抑制和抗肿瘤活性，初步验证了科学假说的可行性。在此基础上，本项目拟对MDM2/HDAC双靶点抗肿瘤先导化合物MHA4，重点开展阐明作用机制、提升双靶点平衡抑制活性、提升成药性能等方面的研究，目标是获得高活性类药分子，为开发多靶点抗肿瘤创新药物奠定基础。

p53-MDM2和HDAC是当前抗肿瘤新药研发的热门靶点，但其单一抑制剂存在疗效有限、毒副作用大等缺陷。鉴于多靶点药物在肿瘤治疗中的诸多优势，本项目基于MDM2/HDAC在生物学功能及其抑制剂在抗肿瘤药效上的协同效应，首次提出了设计MDM2/HDAC双靶抑制剂作为抗肿瘤治疗的新策略。本课题按照研究计划完成了全部研究内容。针对前期发现的新型MDM2/HDAC双靶点抑制剂，完成了3大类抑制剂的分子设计、结构优化、构效关系、体内外抗肿瘤药效研究。设计合成得到110个全新抗肿瘤化合物，从中优选得到3个高活性化合物，在体内模型中显示了优秀的抗肿瘤药效，裸鼠移植瘤体内抑瘤率分别为：65.4%、52.4%和66.6%，显示了良好的成药前景。本项目研究成果为研发多靶点抗肿瘤原创新药提供了成药性先导化合物和候选药物并奠定了理论基础。项目成果在 Journal of Medicinal Chemistry（2篇, IF = 6.253, 7.447）、Acta Pharmaceutica Sinica B（1篇, IF = 11.413）、ACS Medicinal Chemistry Letter（1篇）等期刊发表标注项目资助 SCI 论文5篇，其中影响因子大于6分文章3篇，发表中文核心期刊论文1篇，申请国家发明专利2项，副主编学术专著《药物合成-路线设计策略和案例解析》1部。本项目培养硕士研究生3名，博士研究生1名。项目负责人在项目执行期间获得3项人才计划资助（上海市青年科技英才扬帆计划、时珍青年学者、深蓝工程启航人才计划）和上海市科技进步二等奖（2020年，排名第8）；在中国药学会青年药学论坛学术会议作分会场报告1次，并获得优秀论文二等奖和优秀壁报奖。

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