Design and synthesis of novel HDAC6 inhibitor dimer as HDAC6 degrader for cancer treatment by palladium catalysed dimerisation.

IF 5.6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-02-27 DOI:10.1080/14756366.2025.2468355

Ching Lin, Jui-Ling Hsu, Yu-Tung Hsu, Kuo-Chen Fan, Sian-Siou Wu, Miao-Hsia Lin, Jih-Hwa Guh, Chao-Wu Yu

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引用次数: 0

Abstract

The enigmatic histone deacetylase 6 (HDAC6) is one of a kind among its family. Recent reports revealed that HDAC6 CD1 exhibits E3 ligase activity. Inspired by these researches, we attempted to develop drugs targeting HDAC6 via novel mechanism. Herein, we report a palladium catalysed transformation and purification method for hydroxamic acid dimers, and series of HDAC6 inhibitor-based dimer showing outstanding biological activities and capability of inducing auto-degradation. Our proof-of-concept was highlighted with 2-amino benzamide-based HDAC6 inhibitor dimers that exhibit great HDAC6 inhibition activity (3.9-15.4 nM), good HDAC1/6 selectivity (95-577), and excellent cytotoxicity against human hormone-resistant prostate cancer (HRPC) PC-3 and non-small cell lung cancer (NSCLC) A549 cell lines (5.9-11.3 and 6.6-17.9 μM, respectively) while simultaneously inducing HDAC6 degradation. These dimers not only induce apoptosis and autophagy but also interfere with kinetochore attachment by the detection of BUBR1 phosphorylation at S670.

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新型HDAC6抑制剂二聚体的设计与合成用于钯催化二聚治疗癌症的HDAC6降解剂。

神秘的组蛋白去乙酰化酶6 （HDAC6）是其家族中的一种。最近的报道显示HDAC6 CD1具有E3连接酶活性。受这些研究的启发，我们尝试通过新的机制开发靶向HDAC6的药物。本文报道了一种钯催化转化和纯化羟肟酸二聚体的方法，以及一系列基于HDAC6抑制剂的二聚体，这些二聚体具有出色的生物活性和诱导自降解能力。我们的概念验证是基于2-氨基苯酰胺的HDAC6抑制剂二聚体，具有良好的HDAC6抑制活性（3.9-15.4 nM），良好的HDAC1/6选择性（95-577），对人类激素抵抗性前列腺癌（HRPC） PC-3和非小细胞肺癌（NSCLC） A549细胞系（分别为5.9-11.3和6.6-17.9 μM）具有良好的细胞毒性，同时诱导HDAC6降解。这些二聚体不仅可以诱导细胞凋亡和自噬，还可以通过检测BUBR1在S670位点的磷酸化来干扰着丝点附着。

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

Journal of Enzyme Inhibition and Medicinal Chemistry 医学-生化与分子生物学

CiteScore

10.30

自引率

10.70%

发文量

195

审稿时长

4-8 weeks

期刊介绍： Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.