自噬蛋白LC3B和GABARAP的芳基烷-吲哚酮配体研究

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-01-06 DOI:10.1021/acsmedchemlett.4c0051710.1021/acsmedchemlett.4c00517

Alexandria N. Leveille, Thomas Schwarzrock, Hawley Brown, Bennett True, Joanet Plasencia, Philipp Neudecker, Alina Üffing, Oliver H. Weiergräber, Dieter Willbold and Joshua A. Kritzer*,

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引用次数: 0

摘要

我们首次报道了芳基吡啶-吲哚酮化合物GW5074的结构活性研究，该化合物被报道为自噬相关蛋白LC3B的配体。文献对该化合物的结合亲和力有相互矛盾的信息，并且关于其作为自噬依赖性降解化合物的成分存在一些争论。我们开发了一种alphasgreen实验来测量已知肽配体与LC3B及其类似物GABARAP结合的竞争性抑制。合成了18个类似物，并对这两种蛋白质进行了测试。抑菌力在中高微摩尔范围内。2D-NMR数据显示GABARAP上的结合位点为疏水性口袋1，其中天然肽配体与芳香侧链结合。我们的研究结果表明GW5074以微摩尔亲和力结合LC3B和GABARAP。这些亲和力可以支持进一步探索靶向蛋白降解，但前提是脱靶效应和低溶解度可以得到适当解决。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Exploring Arylidene–Indolinone Ligands of Autophagy Proteins LC3B and GABARAP

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Exploring Arylidene–Indolinone Ligands of Autophagy Proteins LC3B and GABARAP

We report the first structure–activity studies of arylidene–indolinone compound GW5074, which was reported as a ligand of autophagy-related protein LC3B. The literature has conflicting information on the binding affinity of this compound, and there is some debate regarding its use as a component of autophagy-dependent degrader compounds. We developed an AlphaScreen assay to measure competitive inhibition of the binding of known peptide ligands to LC3B and its paralog GABARAP. Eighteen analogs were synthesized and tested against both proteins. Inhibitory potencies were found to be in the mid- to high-micromolar range. 2D-NMR data revealed the binding site on GABARAP as hydrophobic pocket 1, where native peptide ligands bind with an aromatic side chain. Our results suggest that GW5074 binds LC3B and GABARAP with micromolar affinity. These affinities could support further exploration in targeted protein degradation, but only if off-target effects and poor solubility can be appropriately addressed.

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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.