发现首个有效的 DYRK2 蛋白质分解靶向嵌合体降解剂

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-04-30 DOI:10.1021/acsmedchemlett.4c00065

Jian Chen, Wentao Zhu, Wenqian Zhang, Yichen Tong, Fang Xu and Jiyan Pang*,

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引用次数: 0

摘要

双特异性酪氨酸磷酸化调控激酶 2（DYRK2）已被确定为几种癌症的潜在致癌驱动因子，并被认为是重要的癌症治疗靶点。目前已报道了几种 DYRK2 的抑制剂，但尚未发现降解剂。在这项工作中，我们设计并合成了第一个以姜黄素及其类似物为弹头的蛋白水解靶向嵌合体（PROTACs）系列，以靶向降解 DYRK2。降解实验结果表明，化合物 CP134 能有效降低细胞内 DYRK2 的水平（DC50 = 1.607 μM）。进一步的作用机制实验显示，CP134 通过泛素-蛋白酶体系统诱导 DYRK2 降解。总之，本研究揭示的 CP134 是首个强效的 DYRK2 降解剂，可作为进一步评估其治疗潜力的有价值的化学工具。

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Discovery of the First Potent DYRK2 Proteolysis Targeting Chimera Degraders

Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been identified as a promising oncogenic driver of several types of cancer and is considered to be a critical cancer therapeutic target. Several inhibitors of DYRK2 have been reported, but no degraders have been found yet. In this work, we designed and synthesized the first series of proteolysis-targeting chimeras (PROTACs) using curcumin and its analogs as warheads to target and degrade DYRK2. The results of degradation assays showed that the compound CP134 could effectively downregulate the intracellular DYRK2 level (DC₅₀ = 1.607 μM). Further mechanism of action experiments revealed that CP134 induced DYRK2 degradation through the ubiquitin–proteasome system. Altogether, CP134 disclosed in this study is the first potent DYRK2 degrader, which could serve as a valuable chemical tool for further evaluation of its therapeutic potential, and our results broaden the substrate spectrum of PROTAC-based degraders for further therapeutic applications.

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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.