Therapeutic indications for HDAC6 inhibitors in the peripheral and central nervous disorders.

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Expert Opinion on Therapeutic Targets Pub Date : 2024-09-01 Epub Date: 2024-09-20 DOI:10.1080/14728222.2024.2404571
Jonathan van Eyll, Robert Prior, Sylvain Celanire, Ludo Van Den Bosch, Frederik Rombouts
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引用次数: 0

Abstract

Introduction: Inhibition of the enzymatic function of HDAC6 is currently being explored in clinical trials ranging from peripheral neuropathies to cancers. Advances in selective HDAC6 inhibitor discovery allowed studying highly efficacious brain penetrant and peripheral restrictive compounds for treating PNS and CNS indications.

Areas covered: This review explores the multifactorial role of HDAC6 in cells, the common pathological hallmarks of PNS and CNS disorders, and how HDAC6 modulates these mechanisms. Pharmacological inhibition of HDAC6 and genetic knockout/knockdown studies as a therapeutic strategy in PNS and CNS indications were analyzed. Furthermore, we describe the recent developments in HDAC6 PET tracers and their utility in CNS indications. Finally, we explore the advancements and challenges with HDAC6 inhibitor compounds, such as hydroxamic acid, fluoromethyl oxadiazoles, HDAC6 degraders, and thiol-based inhibitors.

Expert opinion: Based on extensive preclinical evidence, pharmacological inhibition of HDAC6 is a promising approach for treating both PNS and CNS disorders, given its involvement in neurodegeneration and aging-related cellular processes. Despite the progress in the development of selective HDAC6 inhibitors, safety concerns remain regarding their chronic administration in PNS and CNS indications, and the development of novel compound classes and modalities inhibiting HDAC6 function offer a way to mitigate some of these safety concerns.

HDAC6 抑制剂在外周和中枢神经疾病中的治疗适应症。
导言:目前,从周围神经病到癌症的临床试验都在探索抑制 HDAC6 的酶功能。选择性 HDAC6 抑制剂发现方面的进展使得研究高效的脑穿透性和外周限制性化合物成为可能,用于治疗 PNS 和 CNS 适应症:本综述探讨了 HDAC6 在细胞中的多因素作用、PNS 和 CNS 疾病的共同病理特征以及 HDAC6 如何调节这些机制。文章分析了药理抑制 HDAC6 和基因敲除/敲低研究作为 PNS 和 CNS 适应症的治疗策略。此外,我们还介绍了 HDAC6 PET 示踪剂的最新进展及其在中枢神经系统适应症中的应用。最后,我们探讨了 HDAC6 抑制剂化合物的进展和挑战,如羟肟酸、氟甲基噁二唑、HDAC6 降解剂和基于硫醇的抑制剂:基于广泛的临床前证据,鉴于HDAC6参与神经变性和衰老相关的细胞过程,药理抑制HDAC6是治疗PNS和CNS疾病的一种很有前景的方法。尽管在开发选择性 HDAC6 抑制剂方面取得了进展,但对其在 PNS 和 CNS 适应症中长期用药的安全性仍存在担忧。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.90
自引率
1.70%
发文量
58
审稿时长
3 months
期刊介绍: The journal evaluates molecules, signalling pathways, receptors and other therapeutic targets and their potential as candidates for drug development. Articles in this journal focus on the molecular level and early preclinical studies. Articles should not include clinical information including specific drugs and clinical trials. The Editors welcome: Reviews covering novel disease targets at the molecular level and information on early preclinical studies and their implications for future drug development. Articles should not include clinical information including specific drugs and clinical trials. Original research papers reporting results of target selection and validation studies and basic mechanism of action studies for investigative and marketed drugs. The audience consists of scientists, managers and decision makers in the pharmaceutical industry, academic researchers working in the field of molecular medicine and others closely involved in R&D.
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