1 International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.
2 Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
OMICS. 2019 Feb;23(2):70-85. doi: 10.1089/omi.2018.0206.
The human epigenome plays a key role in determining cellular identity and eventually function. Drug discovery undertakings have focused mainly on the role of genomics in carcinogenesis, with the focus turning to the epigenome recently. Drugs targeting DNA and histone modifications are under development with some such as 5-azacytidine, decitabine, vorinostat, and panobinostat already approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This expert review offers a critical analysis of the epigenomics-guided drug discovery and development and the opportunities and challenges for the next decade. Importantly, the coupling of epigenetic editing techniques, such as clustered regularly interspersed short palindromic repeat (CRISPR)-CRISPR-associated protein-9 (Cas9) and APOBEC-coupled epigenetic sequencing (ACE-seq) with epigenetic drug screens, will allow the identification of small-molecule inhibitors or drugs able to reverse epigenetic changes responsible for many diseases. In addition, concrete and sustainable innovation in cancer treatment ought to integrate epigenome targeting drugs with classic therapies such as chemotherapy and immunotherapy.
人类表观基因组在决定细胞身份和最终功能方面起着关键作用。药物发现工作主要集中在基因组学在致癌作用中的作用，最近的重点转向了表观基因组。目前正在开发针对 DNA 和组蛋白修饰的药物，其中一些药物，如 5-氮杂胞苷、地西他滨、伏立诺他和帕比司他，已经获得美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）的批准。本专家评论对表观基因组指导的药物发现和开发进行了批判性分析，并对未来十年的机遇和挑战进行了探讨。重要的是，表观遗传编辑技术（如簇状规律间隔短回文重复（CRISPR）-CRISPR 相关蛋白 9（Cas9）和 APOBEC 相关的表观遗传测序（ACE-seq）与表观遗传药物筛选相结合，将能够识别出能够逆转导致许多疾病的表观遗传变化的小分子抑制剂或药物。此外，癌症治疗的具体和可持续创新应该将表观基因组靶向药物与化疗和免疫疗法等经典疗法结合起来。
