BET小分子抑制剂的设计合成及联合siRNA干扰的单载体双靶向复合物的抗白血病作用研究

项目名称： BET小分子抑制剂的设计合成及联合siRNA干扰的单载体双靶向复合物的抗白血病作用研究

项目编号： No.81472780

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李锐

作者单位： 四川大学

项目金额： 78万元

中文摘要： 乙酰化是表观遗传学调节基因转录过程中最重要的方式之一,BET蛋白家族通过N末端的溴结构域阅读乙酰化的组蛋白，然后通过招募转录调节因子到特定基因位点来调控基因的表达。BET家族蛋白与细胞增殖、炎症等疾病相关。前期研究发现五元脲环并香豆素衍生物对BET有一定的抑制作用，为此我们通过骨架迁越的方法将其支链替换成I-BET151的支链，得到了先导 SKLB307403。它对MLL-AF4融合型白血病细胞的抑制活性优于I-BET151。为了增加成药几率，我们不局限在前期发现的五元脲环并香豆素衍生物上，我们拟用药效团及分子对接双重筛选法和骨架迁越法设计合成全新的BET抑制剂。另外为了研究基于BET的双靶治疗白血病的效果，拟利用DexAM载体将自主设计合成的BET抑制剂分别与MDR-1、Plk1和Bcl-2 siRNA联用，以期在BET抗肿瘤的基础上，分别实现抗耐药性、抗肿瘤协同作用以及双重阻断作用

中文关键词： C25_其它肿瘤；BET抑制剂设计合成；siRNA干扰；单载双靶复合物；混合系白血病

英文摘要： Acetylation is an essential component in the epigenetic regulation of gene expression. The bromodomain and extra-terminal domain (BET) family of proteins regulate gene expression through their ability to recognize specific ε-N-acetylmodified lysine residues found within histone tails and than recruit transcription factors. BETs have been associated with numerous conditions including proliferation and inflammation.We have found that the derivatives of coumarin substituted dihydrobenzo[4,5]imidazo[1,2- a]pyrimidin-4-ones could inhibit the BETs. Based on our previous studies, we make the side chains which are found in I-BET151 to replace ours to produce the SKLB307403, which shows the better activity than I-BET151 in MLL-AF4 type leukemia cell. Moreover, to increase the success rate, we are going to investigate the other classes of BET inhibitors with new scaffolds by using pharmacophore search, docking and scaffold hopping.Apart from that, in order to achieve dual targeting anti-tumor effect, we intend to synthesize a single delivery vehicle that not only carries the BET inhibitors but also forms complexes with siRNA molecules (MDR-1, PLK1 and BCL-2 siRNA) to achieve anti-resistance, synergistic effect and dual blocking effect, respectively.

英文关键词： C25_other tumor;Design and synthesis of BET inhibitor;siRNA interference;DexAM complex;mixed lineage leukaemia