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 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.