Liang Hailiu, Li Shuqing, Peng Xiaopeng, Xiao Hao
School of Medical and Information Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 341000, PR China.
School of Medical and Information Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 341000, PR China; Jiangxi Provincial Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou, 341000, PR China.
Eur J Med Chem. 2025 Mar 5;285:117235. doi: 10.1016/j.ejmech.2024.117235. Epub 2025 Jan 3.
Epigenetic dysregulation plays a pivotal role in the initiation and progression of various cancers, influencing critical processes such as tumor growth, invasion, migration, survival, apoptosis, and angiogenesis. Consequently, targeting epigenetic pathways has emerged as a promising strategy for anticancer drug discovery in recent years. However, the clinical efficacy of epigenetic inhibitors, such as HDAC inhibitors, has been limited, often accompanied by resistance. To overcome these challenges, innovative therapeutic approaches are required, including the combination of epigenetic inhibitors with cytotoxic agents or the design of dual-acting inhibitors that target both epigenetic and cytotoxic pathways. In this review, we provide a comprehensive overview of the structures, biological functions and inhibitors of epigenetic regulators (such as HDAC, LSD1, PARP, and BET) and cytotoxic targets (including tubulin and topoisomerase). Furthermore, we discuss recent advancement of combination therapies and dual-target inhibitors that target both epigenetic and cytotoxic pathways, with a particular focus on recent advances, including rational drug design, pharmacodynamics, pharmacokinetics, and clinical applications.
表观遗传失调在各种癌症的发生和发展中起着关键作用，影响着肿瘤生长、侵袭、迁移、存活、凋亡和血管生成等关键过程。因此，近年来靶向表观遗传途径已成为抗癌药物发现的一种有前景的策略。然而，表观遗传抑制剂（如HDAC抑制剂）的临床疗效有限，且常常伴随着耐药性。为了克服这些挑战，需要创新的治疗方法，包括将表观遗传抑制剂与细胞毒性药物联合使用，或设计同时靶向表观遗传和细胞毒性途径的双功能抑制剂。在这篇综述中，我们全面概述了表观遗传调节剂（如HDAC、LSD1、PARP和BET）和细胞毒性靶点（包括微管蛋白和拓扑异构酶）的结构、生物学功能和抑制剂。此外，我们讨论了靶向表观遗传和细胞毒性途径的联合疗法和双靶点抑制剂的最新进展，特别关注包括合理药物设计、药效学、药代动力学和临床应用在内的最新进展。
