Department of Pharmacology, Institute of Pharmacy, I. M. Sechenov First Moscow State Medical University, Moscow, Russia.
Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
Br J Clin Pharmacol. 2021 Dec;87(12):4577-4597. doi: 10.1111/bcp.14889. Epub 2021 May 27.
The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC-inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non-oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA-approved agents; however, it often results in increased treatment-related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising.
组蛋白去乙酰化酶（HDAC）酶是一类表观遗传调节剂，历史上被认为是有吸引力的治疗靶点。在对临床试验趋势进行调查时，我们发现涉及 HDAC 抑制剂的临床试验数量众多，这促使我们进一步评估这类治疗药物的现状。我们总共确定了 32 种具有 HDAC 抑制特性的药物，其中 29 种被发现作为主要治疗靶点与 HDAC 酶相互作用。在这篇综述中，我们概述了临床药物开发，强调了最近的进展，并对特定试验进行了分析，并在适用的情况下分析了化学结构。我们发现血液系统恶性肿瘤仍然是这类药物的主要临床适应证；然而，很明显，这种多样化的趋势正在持续。针对非肿瘤适应证的治疗方法，包括 HIV 感染、肌肉萎缩症、炎症性疾病以及神经退行性疾病，如阿尔茨海默病、额颞叶痴呆和弗里德里希共济失调，正在取得有希望的临床进展。联合治疗方案被证明可提高 FDA 批准药物的反应性；然而，这通常会导致治疗相关毒性增加。这种分析表明，通过大量临床试验，适应证领域正在扩大，同时几个临床前开发领域也很有前景。
