As the most common form of epigenetic regulation by RNA, N6 methyladenosine (m6A) modification is closely involved in physiological processes, such as growth and development, stem cell renewal and differentiation, and DNA damage response. Meanwhile, its aberrant expression in cancer tissues promotes the development of malignant tumors, as well as plays important roles in proliferation, metastasis, drug resistance, immunity and prognosis. This close association between m6A and cancers has garnered substantial attention in recent years. An increasing number of small molecules have emerged as potential agents to target m6A regulators for cancer treatment. These molecules target the epigenetic level, enabling precise intervention in RNA modifications and efficiently disrupting the survival mechanisms of tumor cells, thus paving the way for novel approaches in cancer treatment. However, there is currently a lack of a comprehensive review on small molecules targeting m6A regulators for anti-tumor. Here, we have comprehensively summarized the classification and functions of m6A regulators, elucidating their interactions with the proliferation, metastasis, drug resistance, and immune responses in common cancers. Furthermore, we have provided a comprehensive overview on the development, mode of action, pharmacology and structure–activity relationships of small molecules targeting m6A regulators. Our aim is to offer insights for subsequent drug design and optimization, while also providing an outlook on future prospects for small molecule development targeting m6A.

中文翻译：

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靶向 m6A 调节因子的小分子抑制剂


N6 甲基腺苷 （m6A） 修饰是 RNA 最常见的表观遗传调控形式，与生长发育、干细胞更新和分化以及 DNA 损伤反应等生理过程密切相关。同时，其在癌组织中的异常表达促进了恶性肿瘤的发展，并在增殖、转移、耐药、免疫和预后中发挥重要作用。近年来，m6A 与癌症之间的这种密切关联引起了广泛关注。越来越多的小分子已成为靶向 m6A 调节因子进行癌症治疗的潜在药物。这些分子靶向表观遗传水平，能够精确干预 RNA 修饰并有效破坏肿瘤细胞的存活机制，从而为癌症治疗的新方法铺平道路。然而，目前缺乏对靶向 m6A 调节剂抗肿瘤的小分子的全面综述。在这里，我们全面总结了 m6A 调节因子的分类和功能，阐明了它们与常见癌症中增殖、转移、耐药和免疫反应的相互作用。此外，我们还全面概述了靶向 m6A 调节因子的小分子的开发、作用方式、药理学和构效关系。我们的目标是为后续的药物设计和优化提供见解，同时也为靶向 m6A 的小分子开发的未来前景提供展望。