Development of Ethyl-Hydrazide-Based Selective Histone Deacetylase 6 (HDAC6) PROTACs.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-02-19 eCollection Date: 2025-03-13 DOI:10.1021/acsmedchemlett.5c00033

Daniel Stopper, Irina Honin, Felix Feller, Finn K Hansen

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引用次数: 0

Abstract

Histone deacetylases (HDACs) are promising targets for epigenetic drug discovery. Additionally, targeted degradation of HDACs has emerged as a novel approach in medicinal chemistry and chemical biology. However, most inhibitors and degraders rely on the potentially genotoxic hydroxamate as a zinc-binding group (ZBG). In this study, we present the development of HDAC6-directed proteolysis-targeting chimeras (PROTACs) featuring an ethyl hydrazide moiety as an alternative ZBG. This approach avoids the genotoxicity concerns of hydroxamates while maintaining potent HDAC6 degradation. We synthesized a series of CRBN- and VHL-recruiting PROTACs and identified several potent HDAC6 degraders (HDAC6 D _max > 80%). Among these, 17c was the most effective, achieving an HDAC6 degradation of 91% and a DC₅₀ value of 14 nM. Further characterization proved that 17c acts via the ubiquitin-proteasome system and chemoproteomics confirmed selective HDAC6 degradation over other HDAC isoforms.

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组蛋白去乙酰化酶（HDACs）是表观遗传药物发现领域前景广阔的靶点。此外，有针对性地降解 HDACs 已成为药物化学和化学生物学领域的一种新方法。然而，大多数抑制剂和降解剂都依赖于具有潜在遗传毒性的羟酰胺作为锌结合基团（ZBG）。在本研究中，我们开发了 HDAC6 定向蛋白水解靶向嵌合体（PROTACs），其特点是将乙基酰肼分子作为替代 ZBG。这种方法既避免了羟酰胺类化合物的遗传毒性问题，又能保持强效的 HDAC6 降解作用。我们合成了一系列 CRBN 和 VHL 诱导的 PROTAC，并鉴定出了几种强效 HDAC6 降解剂（HDAC6 D max > 80%）。其中，17c 最为有效，其 HDAC6 降解率达到 91%，DC50 值为 14 nM。进一步的表征证明，17c 是通过泛素-蛋白酶体系统发挥作用的，化学蛋白质组学也证实了它对 HDAC6 的降解具有选择性，而不是对其他 HDAC 同工酶的降解。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.