The flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. All three families of epigenetic proteins-readers, writers, and erasers-are druggable targets that can be addressed through small-molecule inhibitors. At present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. Here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. Finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. To turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design.

中文翻译：

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表观遗传学药物发现的时间表：从现实到梦想。

表观基因组的灵活性引起了一个诱人的争论，即通过药理学治疗探索其逆转作为改善疾病表型的策略。表观遗传蛋白的三个家族（阅读器，书写器和橡皮擦）都是可药物化的靶标，可以通过小分子抑制剂解决。目前，一些靶向表观遗传酶的药物以及表观遗传修饰的类似物已被引入临床用途（例如，用于治疗血液系统恶性肿瘤），并且各种基于表观遗传的药物正在进行临床试验。在这里，我们描述表观遗传药物发现和开发的时间表，从仅基于表型观察的早期设计到使用经过验证的目标进行的最新合理表观遗传药物发现的开始。最后，我们将重点介绍一些需要进一步研究的主要方面，并讨论将表观遗传学药物发现应用于人类疾病的临床管理所需要克服的挑战。为了变为现实，来自各个学科（化学家，生物学家，临床医生）的研究人员需要共同努力，以优化药物工程，读出测定和临床试验设计。