DNA甲基化可以使肿瘤抑制基因失活，从而导致癌症。两种DNA甲基化抑制剂已获得美国食品药品监督管理局（FDA）批准并进入临床使用。然而，这些抑制剂是核苷类似物，可以掺入 DNA 或 RNA 中并引起显着的副作用。 DNMT1 和 DNMT3 是参与 DNA 甲基化的关键酶。在急性髓系白血病模型中，与传统核苷药物相比，非核苷 DNMT1 特异性抑制剂显示出较低的毒性和改善的药代动力学。 DNMT3 还与某些特定癌症有关。因此，开发 DNMT1 或 DNMT3 的非核苷抑制剂有助于了解它们在致癌过程中的作用，并为某些癌症提供靶向治疗选择。尽管尚未有非核苷抑制剂进入临床试验，但在本次综述中，我们重点关注 DNMT1 或 DNMT3 选择性抑制剂。对于 DNMT1 选择性抑制剂，我们整理了通过虚拟筛选确定的再利用药物、衍生化合物和选择性抑制剂的信息。此外，我们还概述了 DNMT1 的潜在靶点，包括蛋白质-蛋白质复合物、RNA 模拟物和适体。与 DNMT1 相比，DNMT3 特异性抑制剂的研究还不够广泛。在这种背景下，我们的探索已经确定了有限数量的分子抑制剂，并且我们提出了特定的长非编码RNA（lncRNA）作为选择性抑制DNMT3的潜在贡献者。这项集体努力旨在为选择性靶向 DNMT1 或 DNMT3 的非核苷抑制剂的开发提供有价值的见解。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

DNA methylation can deactivate tumor suppressor genes thus causing cancers. Two DNA methylation inhibitors have been approved by the Food and Drug Administration (FDA) and have entered clinical use. However, these inhibitors are nucleoside analogues that can be incorporated into DNA or RNA and induce significant side effects. DNMT1 and DNMT3 are key enzymes involved in DNA methylation. In the acute myeloid leukemia model, a non-nucleoside DNMT1-specific inhibitor has shown lower toxicity and improved pharmacokinetics compared to traditional nucleoside drugs. DNMT3 is also implicated in certain specific cancers. Thus, developing non-nucleoside inhibitors for DNMT1 or DNMT3 can help in understanding their roles in carcinogenesis and provide targeted treatment options in certain cancers. Although no non-nucleoside inhibitors have yet entered clinical trials, in this review, we focus on DNMT1 or DNMT3 selective inhibitors. For DNMT1 selective inhibitors, we have compiled information on the repurposed drugs, derivative compounds and selective inhibitors identified through virtual screening. Additionally, we have outlined potential targets for DNMT1, including protein-protein complex, RNA mimics and aptamers. Compared to DNMT1, research on DNMT3-specific inhibitors has been less extensive. In this context, our exploration has identified a limited number of molecular inhibitors, and we have proposed specific long non-coding RNAs (lncRNAs) as potential contributors to the selective inhibition of DNMT3. This collective effort aims to offer valuable insights into the development of non-nucleoside inhibitors that selectively target DNMT1 or DNMT3.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.