Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA.
Neuropharmacology. 2020 Dec 15;181:108306. doi: 10.1016/j.neuropharm.2020.108306. Epub 2020 Sep 15.
Epigenetic pharmacotherapy for CNS-related diseases is a burgeoning area of research. In particular, members of the bromodomain and extra-terminal domain (BET) family of proteins have emerged as intriguing therapeutic targets due to their putative involvement in an array of brain diseases. With their ability to bind to acetylated histones and act as a scaffold for chromatin modifying complexes, BET proteins were originally thought of as passive epigenetic 'reader' proteins. However, new research depicts a more complex reality where BET proteins act as key nodes in lineage-specific and signal-dependent transcriptional mechanisms to influence disease-relevant functions. Amid a recent wave of drug development efforts from basic scientists and pharmaceutical companies, BET inhibitors are currently being studied in several CNS-related disease models, but safety and tolerability remain a concern. Here we review the progress in understanding the neurobiological mechanisms of BET proteins and the therapeutic potential of targeting BET proteins for brain health and disease.
针对中枢神经系统相关疾病的表观遗传药理学治疗是一个新兴的研究领域。特别是，溴结构域和末端结构域（BET）蛋白家族的成员由于其在多种脑部疾病中的潜在作用，已成为引人注目的治疗靶点。由于它们能够与乙酰化组蛋白结合，并作为染色质修饰复合物的支架，BET 蛋白最初被认为是被动的表观遗传“读取器”蛋白。然而，新的研究描绘了一个更为复杂的现实，即 BET 蛋白作为谱系特异性和信号依赖性转录机制中的关键节点，影响与疾病相关的功能。在基础科学家和制药公司最近一波药物研发努力中，BET 抑制剂目前正在几种与中枢神经系统相关的疾病模型中进行研究，但安全性和耐受性仍是一个关注点。在这里，我们综述了对 BET 蛋白的神经生物学机制的理解进展，以及针对 BET 蛋白治疗大脑健康和疾病的治疗潜力。
