基于p53-MDM2/MDMx蛋白-蛋白相互作用双靶点抑制剂的设计、合成及活性评价

The p53 tumor suppressor peptide is a DNA damage responsive transcription factor that closely associated with human cancer, MDM2 and MDMX are two key regulators of p53, and inhibition of p53-MDM2/MDMX protein - protein interactions has gradually become a new target prospect in the study and development of novel anticancer drugs. In order to design and synthesis dual-target inhibitors with good in vitro.and in vivo activities, two classes of promising lead compounds were employed, one was aminothiophene derivatives obtained via our previous study, the other was reported imidazole-based small molecules. The structural features of these two types of molecule scalfolds were fused togther; Then pharmacophore hopping, bioisosteric replacement and the other traditional drug design methods were applied to establish a multi-substituted aromatic heterocyclic virtual compound library. After virtual screening and drug-like analysis, target molecules will get directed synthesis and their binding inhibitory activities of p53-MDM2 and p53-MDMX binding, potencies of induction to tumor cell apoptosis will be evaluated. Structure-activity relationships will be discussed and the effects via the main structural factors will be determined by cellular and molecular level respectively; The mechanism of the target molecules to induce tumor cell apoptosis will be evaluated, and on the basis of in vivo anti-tumor study, 1-2 novel candidate drugs with further development prospects will be strived to find, which will bring out a new aspect for the study and development of multi-targeted anticancer drugs.

p53基因是与人恶性肿瘤相关性最高的肿瘤抑制因子，MDM2与MDMX同源且都为p53关键调节蛋白，抑制p53-MDM2/MDMX蛋白-蛋白相互作用已逐渐成为抗肿瘤药物研究的一个新方向。为设计、合成具有良好体内外活性的双靶点抑制剂，本项目拟以前期所发现的2-氨基噻吩类及文献报道的双靶点抑制剂吲哚-咪唑类小分子为先导化合物，融合两类骨架的结构特征，并利用药效团迁越、电子等排效应等理性药物设计方法，建立多取代杂环类虚拟化合物库，经过虚拟筛选和类药性分析，对其中成药性能良好的目标分子定向合成，并分别从细胞和分子水平评价目标分子对p53-MDM2及p53-MDMX结合抑制活性和诱导肿瘤细胞凋亡的影响，分析构效关系，确定影响活性的主要结构因素；深入探讨目标分子诱导肿瘤细胞凋亡的机理，在动物体内抗肿瘤活性评价的基础上，力争发现1-2个具开发前景的新颖侯选药物，为多靶点抗肿瘤药物的研发提供新的研究思路。

p53基因是与人恶性肿瘤相关性最高的肿瘤抑制因子，MDM2与MDMX同源且都为p53关键调节蛋白，本项目拟以前期所发现的2-氨基噻吩类及文献报道的双靶点抑制剂吲哚-咪唑类小分子为先导化合物，融合两类骨架的结构特征，并利用药效团迁越、电子等排效应等理性药物设计方法，建立多取代杂环类虚拟化合物库，经过虚拟筛选和类药性分析，对其中成药性能良好的目标分子定向合成，并分别从细胞和分子水平评价目标分子对p53-MDM2及p53-MDMX结合抑制活性和诱导肿瘤细胞凋亡的影响，其次为实现MDM2自降解，因此应用PROTAC技术设计、合成了一系列HOMO-PROTAC抑制剂，并测定了所得分子对MDM2的降解能力及其体外抗肿瘤活性，初步研究证实该方法确实能够降解MDM2蛋白产生抗肿瘤作用。另外利用分子碎片化筛选法对其他抗肿瘤靶点的小分子进行了筛选，对该方法进行了拓展。