Dual / bifunctional targeting of bromodomain and extra-terminal (BET) proteins: Expanding the paradigm of epigenetic drug discovery

IF 6.7 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2026-03-05 Epub Date: 2025-12-30 DOI:10.1016/j.ejmech.2025.118524

Fei Jiang , Huili Li , Quan Sun , Jiandong Huang , Xianggui Chen , Qian Liang , Xueyuan Luo , Wenbao Zhang , Dandan He , Xiangchun Shen

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引用次数: 0

Abstract

Bromodomain and extra-terminal (BET) proteins function as key epigenetic regulators of oncogenic, inflammation, and immune pathways, however, their therapeutic targeting has been constrained by limitations of monofunctional inhibitors—notably compensatory resistance, narrow therapeutic indexes, and context-specific efficacy. This review delineates a paradigm shift from occupancy-based inhibition toward multidimensional bifunctional engagement, overcoming these barriers through rationally designed dual-target inhibitors (e.g., BET/HDAC, BET/kinases), catalytic degraders (PROTACs, molecular glues), and pathway-directed systems (autophagy-lysosome modulators, apoptotic reactivators, RIPTACs, and TCIPs). Advanced delivery platforms, including antibody–drug conjugates (ADCs) and stimuli-responsive nanocarriers, may enhance spatiotemporal precision and reduce systemic toxicity. By exploiting synergistic epigenetic-kinase cooperativity or leveraging ternary complex-driven degradation, these innovations are redefining the pharmacological landscape for BET proteins. Collectively, such strategies may provide durable efficacy against recalcitrant cancers, inflammatory disorders, and neurodegenerative diseases, suggesting emerging new design principles for epigenetic therapeutics.

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溴结构域和外端（BET）蛋白的双重/双功能靶向：扩展表观遗传药物发现范式

溴结构域和外端（BET）蛋白是致癌、炎症和免疫途径的关键表观遗传调控因子，然而，它们的治疗靶点受到单功能抑制剂的限制，特别是代偿性耐药、狭窄的治疗指标和环境特异性疗效。这篇综述描述了一种从基于占用的抑制向多维双功能参与的模式转变，通过合理设计双靶点抑制剂（例如，BET/HDAC， BET/激酶），催化降解剂（PROTACs，分子胶）和途径导向系统（自噬溶酶体调节剂，凋亡再激活剂，riptac和tcip）克服这些障碍。先进的递送平台，包括抗体-药物偶联物（adc）和刺激反应性纳米载体，可以提高时空精度并降低全身毒性。通过利用表观遗传激酶协同作用或利用三元络合物驱动的降解，这些创新正在重新定义BET蛋白的药理学景观。总的来说，这些策略可能对顽固性癌症、炎症性疾病和神经退行性疾病提供持久的疗效，这表明表观遗传治疗的新设计原则正在出现。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.