Design and Characterization of a Novel eEF2K Degrader with Potent Therapeutic Efficacy Against Triple-Negative Breast Cancer.
Design and Characterization of a Novel eEF2K Degrader with Potent Therapeutic Efficacy Against Triple-Negative Breast Cancer.
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对三阴性乳腺癌具有有效治疗效果的新型eEF2K降解剂的设计和表征。
DOI：
10.1002/advs.202305035
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发表时间：
2024-02
期刊：
影响因子：
15.1
通讯作者：
Cheng, Yan
中科院分区：
文献类型：
--
作者：
Zhong, Changxin;Zhu, Rongfeng;Jiang, Ting;Tian, Sheng;Zhao, Xiaobao;Wan, Xiaoya;Jiang, Shilong;Chen, Zonglin;Gong, Rong;He, Linhao;Yang, Jin-Ming;Ye, Na;Cheng, Yan
Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple‐negative breast cancer (TNBC), making it a plausible therapeutic target. However, specific eEF2K inhibitors with potent anti‐cancer activity have not been available so far. Targeted protein degradation has emerged as a new strategy for drug discovery. In this study, a novel small molecule chemical is designed and synthesized, named as compound C1, which shows potent activity in degrading eEF2K. C1 selectively binds to F8, L10, R144, C146, E229, and Y236 of the eEF2K protein and promotes its proteasomal degradation by increasing the interaction between eEF2K and the ubiquitin E3 ligase βTRCP in the form of molecular glue. C1 significantly inhibits the proliferation and metastasis of TNBC cells both in vitro and in vivo and in TNBC patient‐derived organoids, and these antitumor effects are attributed to the degradation of eEF2K by C1. Additionally, combination treatment of C1 with paclitaxel, a commonly used chemotherapeutic drug, exhibits synergistic anti‐tumor effects against TNBC. This study not only generates a powerful research tool to investigate the therapeutic potential of targeting eEF2K, but also provides a promising lead compound for developing novel drugs for the treatment of TNBC and other cancers. Dysregulated eukaryotic elongation factor 2 kinase (eEF2K) expression is implicated in the pathogenesis of triple‐negative breast cancer (TNBC). Compound C1 is designed and synthesized, which shows potent activity in degrading eEF2K protein. C1 significantly inhibits the proliferation and metastasis of TNBC. These findings provide a promising therapeutic strategy for the development of novel therapeutic drugs for TNBC treatment.
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