新型P300抑制剂的设计、合成、抗肿瘤活性评价与先导化合物优化方法研究

The histone acetyltransferase P300 is closely related to the development and immune regulation of tumor, which has been considered as a new potential target for antitumor agents. Although there have been some P300 inhibitors, now highly potent and selective P300 inhibitors are still lacking. In the previous study, we established a target-specific virtual screening method, and identified a new potent P300 inhibitor PI-23 using this method. Then, we used the LEADOPT program, a program for lead optimization developed by us, to carry out the preliminary structural optimization for PI-23, and obtained some compounds that are more potent than PI-23. However, the potencies of these compounds are not as good as we expected and evaluations for their selectivity are also needed. Meanwhile, the LEADOPT program still has some shortcomings. Therefore, this project will continue to carry out the following researches: upgrading the LEADOPT program; using the upgraded program, chemical synthesis, biological activity testing, X-ray diffraction analysis and other methods to further optimize the chemical structure of PI-23, with the aim to obtain highly potent and selective P300 inhibitors; evaluating the antitumor activity of P300 inhibitors and exploring their molecular mechanism of action. The implementation of this project will be possible to provide a more effective method for lead optimization and lay a certain foundation for P300-targeted antitumor drug research.

组蛋白乙酰基转移酶P300与肿瘤发生发展及肿瘤免疫调节密切相关，是一个潜在的抗肿瘤新靶标。虽然已有一些抑制剂报道，但目前十分缺乏高活性和选择性的P300抑制剂。为此，申请人构建了一种靶标特异性虚拟筛选方法，筛选得到了一个新型P300抑制剂PI-23，并通过自主发展的先导化合物优化LEADOPT程序对其进行初步的结构优化，获得了一些活性优于PI-23的化合物。然而，它们的活性并未达到我们预期的结果，选择性也有待考察，同时LEADOPT仍存在一些不足。鉴于此，本项目接下来将开展以下研究：对LEADOPT进行升级；利用升级后的程序、化学合成、生物活性测试、单晶X射线衍射等方法，继续对PI-23进行结构优化，以期获得高活性和选择性P300抑制剂；对优化获得的P300抑制剂进行抗肿瘤活性及分子机制研究。本项目的实施将有可能为先导化合物优化提供更有效的方法，为靶向P300的抗肿瘤药物研究奠定一定基础。

组蛋白乙酰基转移酶p300与肿瘤发生发展及肿瘤免疫调节密切相关，是一个潜在的抗肿瘤新靶标。本项目发展了基于蛋白-小分子相互作用的指纹图谱的靶标特异性虚拟筛选IFPanalyses方法和靶标预测IFPTarget方法，完成了先导化合物优化LEADOPT程序的升级。利用这些方法，针对p300 HAT结构域的特征，对构建的集中化合物库和天然产物库，开展了虚拟筛选研究，发现了多个苗头化合物和天然产物对p300 HAT有较好地抑制活性，并对这些化合物进行了结构优化设计，共合成了80余个化合物，其中部分化合物对p300 HAT的抑制活性为纳摩尔水平。此外，利用发展的方法，针对p300 HAT机制相关的Sirtuin家族及抗生素耐药酶MBL，发现了多个活性或先导化合物，进一步验证了发展的药物设计方法的有效性。本项目为先导化合物发现和优化提供更有效的方法，为靶向p300 HAT的抗肿瘤药物研究提供了新的先导化合物。以第一或通讯作者在Chem Sci、Eur J Med Chem、J Chem Inf Model、Org Chem Front、Bioorg Med Chem Lett、MedChemComm等杂志发表基金标注SCI论文15篇，申请中国发明专利4项，在2017年中国药物化学学术会议和2018年世界华人药物化学研讨会获优秀报告奖。