p53是迄今发现与人肿瘤发生相关性最高的抑癌基因。MDM2蛋白与p53结合抑制其功能，导致肿瘤发生及转移，设计阻断两者作用的小分子具有非常重要的意义。本课题前期以此为靶点，使用CCAD联合SPR的方法筛选化合物库，得到先导物LJ1019，未见此类结构被报道具有抗肿瘤活性，经免疫共沉淀实验验证机制，细胞实验IC50值与阳性对照nutlin-3a相当，体内实验有效。LJ1019结构新颖，靶点明确，抗肿瘤活性确切，结构改造空间大。本项目根据LJ1019与MDM2蛋白对接构象，利用基于受体结构骨架跃迁及优势骨架导向的方法对其进行结构优化，设计合成6类全新骨架衍生物，力求提升活性及成药性。构建荧光偏振法快速、准确、定量评价衍生物抑制活性，使用小鼠乳腺癌转移瘤活体照相模型进行体内评价。以期得到基于MDM2-p53相互作用，活性更强，构效关系明确，药代优异，体内有效抑制肿瘤生长及转移的先导物。

p53 is a powerful tumor suppressor and is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. The gene encoding p53 protein is mutated or deleted in half of human cancers, which inactivates its tumor suppressor activity. In the remaining cancers, p53 retains its wild-type form but its activity is effectively inhibited through direct interaction with the human murine double minute 2 (MDM2) oncoprotein. Blocking the MDM2-p53 interaction to reactivate the p53 function is a promising cancer therapeutic strategy. In our preliminary work, an integrated virtual database screening strategy, which combined both pharmacophore based and structure based (docking) method, and SPR were employed to identify compound LJ1019 as MDM2-p53 interaction inhibitor with novel scaffold. Additionally, LJ1019 showed antiproliferative activity against HCT116, A549 and MCF7 cell lines possessing wild-type p53 with IC50 values was comparable to that of reference drug natlin-3a. Based on those preliminary results, in this proposal, LJ1019 was chosen as the hits compound, and structure-based hits optimization was carried on based on its docking pose in the binding pocket of MDM2 by using scaffold hopping and privileged structures-oriented method,in order to discover promising lead compounds with potent antiproliferative activity and superior physicochemical and ADMET profiles, and pave the way for the development of novel anticancer drugs.