Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China.
Signal Transduct Target Ther. 2024 Nov 26;9(1):332. doi: 10.1038/s41392-024-02039-0.
Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.
DNA 修饰、组蛋白修饰、RNA 修饰、染色质重塑和非编码 RNA 调控。这些机制及其相关酶独立于 DNA 碱基序列传递遗传信息，在生物发育和内稳态中发挥着重要作用。相反，表观遗传景观的破坏会严重影响各种人类疾病的发病机制。这种理解为开发针对病理条件下的表观遗传修饰酶的药物奠定了坚实的理论基础。在过去的二十年中，针对表观遗传酶（如 DNA 甲基转移酶、组蛋白去乙酰化酶、异柠檬酸脱氢酶和 EZH2 等）的小分子药物的研究不断深入，并已作为治疗选择得到了广泛应用，尤其是在肿瘤学领域。此外，许多针对表观遗传学的药物正在进行临床试验，为临床获益提供了广阔的前景。本综述阐述了表观遗传学在生理和病理背景下的作用，并强调了在发现和临床实施表观遗传学药物方面的开创性研究。这些研究包括抑制剂、激动剂、降解剂和多靶标药物，旨在确定实际挑战和未来研究的有前途的途径。最终，本综述旨在加深对基于表观遗传学的治疗策略的理解，并进一步将其应用于临床环境中。
