组蛋白乙酰转移酶hMOF抑制剂的发现及抗肿瘤作用机制研究

Epigenetic regulation is of therapeutic relevance in multiple diseases such as cancer, inflammation, and metabolic diseases. Histone acetylation is one of the important epigenetic regulation, which regulated by histone acetyltransferase and histone deacetylase. Histone acetyltransferase hMOF (human male absent on the first) inhibitors regulate the histone acetyltion and inhibit the tumor growth. As far as we know, there is no hMOF inhibitor up to now, therefore, discovery and development of hMOF specific inhibitors is very important for clinical significance and practical applications. In our previous studies, a series of novel hMOF inhibitors were discovered by computer aided drug design and screening the drug-like privileged compound library, based on molecula/cell biology chemistry verification platform. In this project, we will carry out a full SAR study for the hit compound A-64, and obtain some more biologically active lead compounds via lead optimization, further biological assay, pharmacokinetic study, and safety evaluation. In addition, this program also aims to detect the expression of hMOF protein in colorectal carcinoma to analyze their correlations, and explore the significance and the mechanism of their expression in rectal cancer. Based on these findings, we hope to find new biologic markers of cancer, so that we can provide novel theoretical evidence for the prediction, early-stage dignoses, prognosis, and drug treatment of rectal cancer.

表观遗传学调节的异常与肿瘤、炎症、代谢性疾病等严重危害人类健康的疾病密切相关。组蛋白乙酰化是表观遗传修饰途径之一，由组蛋白乙酰转移酶和组蛋白去乙酰化酶调控。基于组蛋白乙酰转移酶hMOF进行药物设计，通过干扰组蛋白乙酰化水平可有效抑制肿瘤细胞生长。由于目前尚未发现hMOF抑制剂，因此，寻找hMOF特异性抑制剂具有重要的临床意义和应用前景。在前期研究中，基于药物设计结合已建立的"优势骨架化合物库"和分子/细胞化学生物学验证平台，首次获得一类新型hMOF抑制剂，证明本课题的研究策略切实可行。本项目中，我们拟对"苗头"化合物A-64进行结构修饰与优化，获得结构新颖、高效、高特异性的类药性化合物用于结肠癌的治疗，为开发具有自主知识产权的创新药物奠定基础；同时，探讨结肠癌组织中hMOF的表达，分析hMOF在结肠癌发生发展中的作用机制，为临床对结肠癌进行早期诊断、愈后判断、指导治疗提供新的理论依据。

本项目针对已构建的“类药性优势骨架化合物库”开展基于结构的虚拟筛选，结合分子水平和细胞水平的药理活性筛选，通过运用经典的药物化学结构优化方法，开发获得百余个结构新颖的hMOF小分子抑制剂。我们采用高效的不对称有机合成技术，丰富了该化合物库的小分子结构多样性，尤其针对药物分子中常见的非天然氨基酸结构片段进行了合成方法学研究，利用镍螯合物的高对映选择性特点，设计合成了结构多样、种类丰富的非天然氨基酸，丰富了类药性优势骨架化合物库的结构多样性。基于前期开发获得的活性分子进行结构优化，设计合成了百余个结构新颖的hMOF小分子抑制剂，通过建立hMOF活性筛选平台，开展系统的药效学评价筛选，开发获得高活性、高选择性的hMOF小分子抑制剂，同时开展了抗肿瘤作用机制研究，为hMOF小分子抑制剂研究奠定基础。. 在本项目执行期间（2015.1-2018.12），在Angew. Chem. Int. Ed.、Eur. J. Med. Chem.、J. Org. Chem.等国际重要学术期刊发表相关学术论文10篇，影响因子48。培养博士研究生2名，硕士研究生3名，建立了一支充满创新活力的研究团队。

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