Discovery of the First Potent DYRK2 Proteolysis Targeting Chimera Degraders,ACS Medicinal Chemistry Letters

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Discovery of the First Potent DYRK2 Proteolysis Targeting Chimera Degraders
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2024-04-30 , DOI: 10.1021/acsmedchemlett.4c00065
Jian Chen ₁ , Wentao Zhu ₁ , Wenqian Zhang ₁ , Yichen Tong ₁ , Fang Xu ₂ , Jiyan Pang ₁

Affiliation

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.

中文翻译：

发现第一个针对嵌合体降解剂的有效 DYRK2 蛋白水解作用

双特异性酪氨酸磷酸化调节激酶 2 (DYRK2) 已被确定为多种类型癌症的有前景的致癌驱动因素，并被认为是关键的癌症治疗靶点。已报道了几种 DYRK2 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系列蛋白水解靶向嵌合体（PROTAC），使用姜黄素及其类似物作为弹头来靶向和降解 DYRK2。降解实验结果表明，化合物CP134可以有效下调细胞内DYRK2水平（DC ₅₀ = 1.607 μM）。进一步的作用机制实验表明， CP134通过泛素-蛋白酶体系统诱导 DYRK2 降解。总而言之，本研究中公开的CP134是第一个有效的 DYRK2 降解剂，它可以作为进一步评估其治疗潜力的有价值的化学工具，我们的结果拓宽了基于 PROTAC 的降解剂的底物谱，用于进一步的治疗应用。

更新日期：2024-04-30

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