Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-10-01 DOI:10.1021/acsmedchemlett.4c0025510.1021/acsmedchemlett.4c00255

Rui Yang, Betsy Pray, Lapo Alinari*, Pui Kai Li* and Xiaolin Cheng*,

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引用次数: 0

Abstract

Transducin β-like protein 1 X-linked (TBL1X) is an essential scaffold protein involved in multiple signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Recent studies, however, suggest that TBL1X might modulate Wnt-regulated genes independently of β-catenin in diffuse large B-cell lymphoma (DLBCL). Here, we developed selective TBL1X degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy as a proof-of-concept. Eight PROTACs showed strong cytotoxic activity. Interestingly, N-linked PROTACs exhibited minimal TBL1X degradation, while most O-linked PROTACs significantly reduced TBL1X levels, suggesting the crucial role of the linker attachment site in successful TBL1X degradation. Our mechanistic study revealed that TBL1X degradation induced by TD11 relied on the formation of the ternary complex and was dependent on the proteasome. The TBL1X degraders developed in this study could be a valuable chemical tool for investigating TBL1X-related pathways.

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选择性 TBL1X 降解剂的设计、合成和生物学评估

转导蛋白β样蛋白1 X-连锁（TBL1X）是一种重要的支架蛋白，参与多种信号通路，如Wnt/β-catenin通路，它保护β-catenin免于泛素化和蛋白酶体降解。然而，最近的研究表明，在弥漫大B细胞淋巴瘤（DLBCL）中，TBL1X可能独立于β-catenin而调节Wnt调控基因。在此，我们利用蛋白水解靶向嵌合体（PROTACs）策略开发了针对DLBCL的选择性TBL1X降解剂，作为概念验证。8种PROTACs显示出很强的细胞毒活性。有趣的是，N-连接的PROTACs对TBL1X的降解作用极小，而大多数O-连接的PROTACs则能显著降低TBL1X的水平，这表明连接体的连接位点在成功降解TBL1X中起着至关重要的作用。我们的机理研究发现，TD11诱导的TBL1X降解依赖于三元复合物的形成，并且依赖于蛋白酶体。本研究开发的 TBL1X 降解剂可能是研究 TBL1X 相关途径的一种有价值的化学工具。

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.