Comprehensive whole-exome sequencing, DNA copy-number determination, and transcriptomic analyses of diverse cancers have greatly expanded our understanding of the biology of many tumor types. In addition to mutations in the common cell-of-origin specific driver mutations, these studies have also revealed a large number of loss-of-function and gain-of-function mutations in chromatin-modifying proteins (CMPs). This has revealed that epigenetic dysregulation is a common feature of most pediatric and adult cancers. Many specific and potent inhibitors have been developed for multiple CMP classes, which have assisted in elucidating the role of epigenetics as well as epigenetic vulnerabilities in these cancer types. Clinical trials with numerous CMP inhibitors are also currently in progress to evaluate the therapeutic potential of epigenetic inhibitors. In this review, we aim to provide a summary of genetic mutations in epigenetic genes and a review of CMP inhibitors suitable for preclinical studies or currently in clinical trials. Additionally, we highlight the CMPs for which potent inhibitors have not been developed and additional research focus should be dedicated.

中文翻译：

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癌症表观遗传学的药物发现和化学生物学

全面的全外显子组测序，DNA拷贝数测定和各种癌症的转录组分析，极大地扩展了我们对许多肿瘤类型生物学的理解。除了常见的起源细胞特定的驱动程序突变中的突变外，这些研究还揭示了染色质修饰蛋白（CMP）中大量的功能丧失和功能获得性突变。这表明表观遗传失调是大多数儿科和成年癌症的共同特征。已经针对多种CMP类别开发了许多特异性和有效的抑制剂，这些抑制剂有助于阐明表观遗传学的作用以及这些癌症类型中表观遗传学的脆弱性。目前也正在进行许多CMP抑制剂的临床试验，以评估表观遗传抑制剂的治疗潜力。在这篇综述中，我们旨在提供表观遗传基因中遗传突变的摘要以及适用于临床前研究或当前正在临床试验中的CMP抑制剂的综述。此外，我们重点介绍了尚未开发出强效抑制剂的CMP，并应特别关注其他研究领域。