A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours.

中文翻译：

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寻求更精确的癌症治疗方法：探索表观遗传学的复杂性。

大量的临床前证据表明，针对表观遗传失调的药理学靶向是对抗人类疾病的有效策略。然而，在临床实践中使用表皮药物非常稀少，并且主要限于血液系统恶性肿瘤。在这篇综述中，我们讨论了促进策略设计的化学设计，生物学原理和临床试验开发的前沿策略。具体来说，我们专注于双重杂交的开发，以利用在癌症中失活的关键表观遗传分子的多靶点；表观遗传合成致死性相互作用作为解决功能丧失突变的机制的研究，以及将表皮药物与其他疗法（例如免疫疗法）结合使用，以避免获得性化学耐药性并提高治疗敏感性。通过探索这些挑战，