基于分子片段发现和优化先导化合物确认若干组蛋白识别、修饰相关靶点

Epigenetics, including histone recognition and modification, is a subject studying the processes that do not change the DNA sequence but can inherit the genetic information. It relates to many complex diseases, and now become the hot-spot in drug discovery field. The present proposal is based on our previous works of fragment-based drug discovery(FBDD) technology, which integrating computer aided drug design, structural biology and medicinal chemistry. We selected four representative targets from epigenetics, and will identify the hit fragments with our FBDD platform. Therefore we can set up to lead optimization with the aim to find high potent, high selective compounds as tool to validate the targets. The validation will be from four levels, including molecular, cellular, phenotype and in vivo animal model studies. In current stage, we have finished all the gene clone, protein expression and purification for four proteins. Also for BRD4, we have performed the FBDD study and obtained 9 active fragments by diffracting about 60 crystals. For the SUV39H1, we have investigated the effects of drug combinations between SUV39H1 inhibitor and several first line drugs for treating several cancer cell lines. The results show that SUV39H1 inhibitor is synergic and effective in all cases. We hope the present proposal can stimulate the drug research on epigenetic targets, and will be beneficial for future drug development.

表观遗传学，其中包括组蛋白识别、修饰的调控，是DNA序列没有发生改变情况下发生可以遗传的遗传信息变化。其与多种疾病密切相关，成为继激酶之后药物创新激烈竞争的领域。本课题在前期研究基础上完善和发展基于片段药物发现新方法，融计算机辅助药物设计、结构生物学、药物化学于一体，针对4个组蛋白识别、修饰相关蛋白，发现和优化具有高选择性、高活性、成药性质的小分子配体；通过酶活性、细胞增殖活性测试，细胞功能、表型、机理研究；整体动物药效验证，推进其成为潜在药物靶点的确认研究。在本课题前期完成各蛋白表达纯化；开展部分复合物结构生物学研究，发现BRD4高活性新颖结构化合物；此外还发现SUV39H1抑制剂与临床一线药物联合使用显示良好的协同作用，在明显降低H3K9me3水平的同时，对胰腺癌、肝癌、三阴乳腺癌等缺乏临床治疗药物的肿瘤细胞株具有较强的细胞增殖抑制活性。希望通过本课题研究为该类药物原始性创新奠定基础。

表观遗传学，其中包括组蛋白识别、修饰的调控，是DNA序列没有发生改变情况下发生可以遗传的遗传信息变化。其与多种疾病密切相关，成为继激酶之后药物创新激烈竞争的领域。本课题在前期研究基础上完善和发展基于片段药物发现新方法，融计算机辅助药物设计、结构生物学、药物化学于一体，针对多个组蛋白识别、修饰相关蛋白，发现和优化具有高选择性、高活性、成药性质的小分子配体；并通过酶活性、细胞增殖活性测试，细胞功能、机理研究以及整体动物药效验证，推进其成为潜在药物靶点的确认研究。目前我们已经建立完善了片段设计平台，拥有1500个片段分子和多种片段筛选方法。我们在BRD4和LSD1抑制剂研究中获得了多个候选药物，目前正积极评价，近期将推进开展系统临床前研究。