Targeted Histone Deacetylase Degradation via Chemical Induced Proximity by Direct Recruitment of the CUL4 Complex Adaptor Protein DDB1

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-09-16 DOI:10.1021/acsmedchemlett.5c00506

Shiyang Zhai, , , Nicola Willemsen, , , Tao Sun, , , Mateo Malenica, , , Shixin Deng, , , Matthias Geyer, , and , Finn K. Hansen*,

引用次数: 0

Abstract

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as a powerful strategy for disease treatment. By recruiting E3 ligases, these molecules enable selective degradation of pathogenic proteins. Cereblon (CRBN), a key component of the CUL4-DDB1-CRBN E3 ligase complex, is the most commonly recruited E3 ligase in PROTACs, including those targeting histone deacetylases (HDACs). In this study, we designed SZ-2, a bifunctional molecule derived from the DDB1 ligand MM-02-57 and the HDAC inhibitor vorinostat, to simultaneously bind DDB1 and HDACs. SZ-2 effectively induced degradation of HDAC1 and HDAC2 and demonstrated potent anti-multiple myeloma activity, highlighting its potential as a novel therapeutic agent.

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通过直接募集CUL4复合体接头蛋白DDB1的化学诱导接近靶向组蛋白去乙酰化酶降解

利用靶向蛋白水解嵌合体（proteolysis-targeting chimeras, PROTACs）进行靶向蛋白降解已成为疾病治疗的一种强有力的策略。通过招募E3连接酶，这些分子能够选择性地降解致病蛋白。Cereblon （CRBN）是CUL4-DDB1-CRBN E3连接酶复合物的关键组分，是PROTACs中最常见的E3连接酶，包括靶向组蛋白去乙酰化酶（hdac）的PROTACs。在本研究中，我们设计了由DDB1配体MM-02-57和HDAC抑制剂vorinostat衍生的双功能分子SZ-2，用于同时结合DDB1和HDAC。SZ-2有效诱导HDAC1和HDAC2的降解，并显示出有效的抗多发性骨髓瘤活性，突出了其作为新型治疗剂的潜力。

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

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.