高选择性HDAC1抑制剂的发现、优化和抗肿瘤活性研究

Histone deacetylases (HDACs) have been identified as attractive targets particularly for cancer therapy. However, all of these agents have significant toxicity, including thrombocytopenia. Thus, selective HDAC1 inhibitors may be tolerated better and cause fewer adverse reactions. However, rational design of selective HDAC1 inhibitors is a challenging task because of the high structural similarity among HDACs. In our previous studies, compound 33a was obtained by rational design, which showed good inhibitory activty against HDAC1 but weak inhibitory potency against other isoforms of HDACs. Compound 33a showed potent antitumor efficacy in vitro and in vivo and good stability in liver microsomal enzymes. Inspired by these results, this study aims to discover selective HDAC1 inhibitors with high selectivity, excellent antineoplastic activity and good drug-like properties, using rational drug design based on ligand-receptor binding mode, followed by improving antitumor activity and drug-like property simultaneously. As a result, the anticancer mechanisms and in vivo antitumor features of these candidates will be clarified. This project will obtain anticancer NCEs or anticancer candidate drugs, laying foundations for discovery of innovative, highly effective antitumor agents targeting HDAC1 with our own intellectual property rights and providing small molecular probes for the intensive study of the biological function of HDAC1.

组蛋白去乙酰化酶（HDAC）是重要的抗肿瘤靶点，但是由于现有抑制剂缺乏对HDAC各亚型的选择性，往往导致血小板减少症等严重的毒副作用。选择性HDAC1抑制剂将有望改善这一现状，提高药物耐受性。由于HDAC各亚型的结构相似性，选择性HDAC1抑制剂的设计面临较大挑战。本课题前期发现高活性高选择性HDAC1抑制剂33a，仅对HDAC1具有较强抑制作用，对HDAC其他亚型活性微弱或完全无活性。该化合物具有优秀的体内外抗肿瘤活性和良好的肝微粒体酶稳定性。在此基础上，本课题基于“受体-配体”结合模式对先导化合物开展合理药物设计，通过活性和类药性质同步优化策略，获得选择性高、活性好、成药性质优的抗肿瘤新化学实体或者候选药物。在此基础之上阐明其作用机制和体内抗肿瘤药效特点，为创制具有自主知识产权的高活性HDAC1抑制剂，开发抗肿瘤新药奠定基础，为HDAC1生物学功能的深入研究提供小分子探针。

组蛋白去乙酰化酶（HDAC）是重要的抗肿瘤靶点，但是由于现有抑制剂缺乏对HDAC各亚型的选择性，往往导致血小板减少症等严重的毒副作用。选择性HDAC1抑制剂将有望改善这一现状，提高药物耐受性。但研发HDAC1选择性抑制剂面临很大挑战。本项目以吴茱萸碱母核为骨架，在分析Top酶和HDAC各亚型结构及化合物作用模式基础上，在吴茱萸碱骨架引入HDAC药效团，通过药效团融合、分子对接和动力学计算，设计合成4类HDAC抑制剂102个，大部分化合物具有优秀的HDAC1抑制活性，部分化合物的抑制活性达到纳摩尔级，并表现出较好的选择性。其中，化合物C23a是首个报道的Top2/HDAC1亚型选择性双靶点抑制剂，通过Top2和HDAC1的协同效应有效抑制HCT116肿瘤生长，在结肠癌HCT116裸鼠移植瘤体内抑瘤率达到75%，显著优于上市药SAHA和组合给药组，且毒副作用小安全性高。药代动力学实验显示C23a在血浆中的暴露水平良好，并具有良好的代谢稳定性，有望作为候选药物进行开发。化合物C11h对HDAC1和HDAC2的选择性达131倍，对白血病细胞株K562表现出最佳抗肿瘤活性(IC50 = 125 nM)。在本项目资助下，共发表SCI论文9篇，其中影响因子10分以上3篇，5-10分3篇，申请国家发明专利2项；培养博士研究生2名，硕士研究生2名。项目负责人入选军队高层次青年科技英才和3项省部级人才计划（上海市青年拔尖人才、上海市青年科技启明星、上海市人才发展资金）。

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