癌细胞展示出广泛的DNA甲基化变化、组蛋白翻译后修饰的破坏性模式、染色质组成或组织以及调节元素活性，这些改变改变了基因表达的正常程序。越来越清楚的是，表观基因组的紊乱是癌症的标志，是可靶向的，并且是药物创制的有吸引力的起点。在过去的几十年里，在发现和开发基于表观遗传学的小分子抑制剂方面取得了显著的进展。最近，在血液系统恶性肿瘤和实体瘤中鉴定出了靶向表观遗传的药物，这些药物目前正在进行临床试验或已被批准用于治疗。然而，表观遗传药物应用面临许多挑战，包括低选择性、生物利用度差、不稳定以及获得药物耐药性。正在设计新的多学科方法来克服这些限制，例如应用机器学习、药物再利用、高通量虚拟筛选技术，以识别具有改进稳定性和更好的生物利用度的选择性化合物。我们概述了调节表观遗传的关键蛋白质，包括组蛋白和DNA修饰，并讨论影响染色质结构和功能的效应器蛋白质以及目前可用的抑制剂作为潜在药物。突出显示了世界范围内治疗监管机构批准的靶向表观遗传修饰酶的抗癌小分子抑制剂。其中许多处于不同阶段的临床评估中。我们还评估了表观遗传药物与免疫治疗、标准化疗或其他类药物的联合应用以及新型表观遗传治疗设计的进展。 版权所有©2023 Elsevier Inc.

Cancer cells display pervasive changes in DNA methylation, disrupted patterns of histone posttranslational modification, chromatin composition or organization and regulatory element activities that alter normal programs of gene expression. It is becoming increasingly clear that disturbances in the epigenome are hallmarks of cancer, which are targetable and represent attractive starting points for drug creation. Remarkable progress has been made in the past decades in discovering and developing epigenetic-based small molecule inhibitors. Recently, epigenetic-targeted agents in hematologic malignancies and solid tumors have been identified and these agents are either in current clinical trials or approved for treatment. However, epigenetic drug applications face many challenges, including low selectivity, poor bioavailability, instability and acquired drug resistance. New multidisciplinary approaches are being designed to overcome these limitations, e.g., applications of machine learning, drug repurposing, high throughput virtual screening technologies, to identify selective compounds with improved stability and better bioavailability. We provide an overview of the key proteins that mediate epigenetic regulation that encompass histone and DNA modifications and discuss effector proteins that affect the organization of chromatin structure and function as well as presently available inhibitors as potential drugs. Current anticancer small-molecule inhibitors targeting epigenetic modified enzymes that have been approved by therapeutic regulatory authorities across the world are highlighted. Many of these are in different stages of clinical evaluation. We also assess emerging strategies for combinatorial approaches of epigenetic drugs with immunotherapy, standard chemotherapy or other classes of agents and advances in the design of novel epigenetic therapies.Copyright © 2023 Elsevier Inc. All rights reserved.