Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-11-01 DOI:10.1016/j.ejmech.2024.117016

Chaowei Wen , Prathibha R. Gajjala , Yihan Liu , Bingzhong Chen , Mehtab S. Bal , Payal Sutaria , Qiao Yuanyuan , Yang Zheng , Yang Zhou , Jinwei Zhang , Weixue Huang , Xiaomei Ren , Zhen Wang , Ke Ding , Arul M. Chinnaiyan , Fengtao Zhou

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Abstract

Pseudokinase TRIB2, a member of the CAMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder 1 with VHL or CRBN ligands via linkers of varying lengths and compositions. Among these compounds, 5k demonstrated potent TRIB2 degradation with a DC₅₀ value of 16.84 nM (95 % CI: 13.66–20.64 nM) in prostate cancer PC3 cells. Mechanistic studies revealed that 5k directly interacted with TRIB2, selectively inducing its degradation through a CRBN-dependent ubiquitin-proteasomal pathway. Moreover, 5k outperformed the TRIB2 binder alone in inhibiting cell proliferation and inducing apoptosis, confirming that TRIB2 protein degradation could be a promising therapeutic strategy for TRIB2-associated cancers. Additionally, compound 5k also serves as an effective tool for probing TRIB2 biology.

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发现首个针对伪激酶 TRIB2 的选择性强效 PROTAC 降解剂

伪激酶 TRIB2 是 CAMK Ser/Thr 蛋白激酶家族的成员，通过磷酸化无关机制调节各种细胞过程。TRIB2 的失调与促进肿瘤生长、转移和耐药性有关，因此是一个很有前景的癌症治疗靶点。在这项研究中，我们设计并合成了一系列 TRIB2 PROTAC 降解剂，方法是通过不同长度和组成的连接体将 TRIB2 结合剂 1 与 VHL 或 CRBN 配体连接。在这些化合物中，5k 对前列腺癌 PC3 细胞的 TRIB2 降解效果显著，DC50 值为 16.84 nM（95% CI：13.66 - 20.64 nM）。机理研究显示，5k 与 TRIB2 直接相互作用，通过依赖 CRBN 的泛素-蛋白酶体途径选择性地诱导其降解。此外，5k 在抑制细胞增殖和诱导细胞凋亡方面的表现优于单独的 TRIB2 结合剂，这证实了 TRIB2 蛋白降解可能是治疗 TRIB2 相关癌症的一种有前景的策略。此外，化合物 5k 还是探究 TRIB2 生物学特性的有效工具。

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

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.