Structure–Activity Relationship Studies of Substituted 2-Phenyl-1,2,4-triazine-3,5(2H,4H)-dione Analogues: Development of Potent eEF2K Degraders against Triple-Negative Breast Cancer,Journal of Medicinal Chemistry

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Structure–Activity Relationship Studies of Substituted 2-Phenyl-1,2,4-triazine-3,5(2H,4H)-dione Analogues: Development of Potent eEF2K Degraders against Triple-Negative Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-29 , DOI: 10.1021/acs.jmedchem.4c01484
Xiaobao Zhao ₁ , Changxin Zhong _{2,

3} , Rongfeng Zhu ₁ , Rong Gong _{2,

3} , Bingyan Liu ₁ , Linhao He _{2,

3} , Sheng Tian _{1,

4} , Jing Jin ₁ , Ting Jiang _{2,

3} , Jing-Lei Chen ₁ , Xiaoya Wan _{2,

3} , Wenjing Liu ₁ , Shilong Jiang ₅ , Pan Deng ₁ , Yan Cheng _{2,

3,

6} , Na Ye _{1,

4}

Affiliation

eEF2K, an atypical alpha-kinase, is responsible for regulating protein synthesis and energy homeostasis. Aberrant eEF2K function has been linked to various human cancers, including triple-negative breast cancer (TNBC). However, limited cellular activity of current eEF2K modulators impedes their clinical application. Based on the 2-phenyl-1,2,4-triazine-3,5(2H,4H)-dione scaffold of our hits I4 and C1, structure–activity relationship analysis led to the discovery of several more active derivatives (e.g., 19, 34, and 36) in inhibiting the viability of TNBC cell line MDA-MB-231. Moreover, the most potent compound 36 significantly suppresses the viability, proliferation, and migration of both MDA-MB-231 and HCC1806 cell lines. Mechanistically, compound 36 has a high binding affinity for the eEF2K protein and effectively induces its degradation. Additionally, 36 exerts a comparable tumor-suppressive effect to paclitaxel in an MDA-MB-231 cell xenograft mouse model with no obvious toxicity, demonstrating that compound 36 could be developed as a potential novel therapeutic for TNBC treatment.

中文翻译：

取代的 2-苯基-1,2,4-三嗪-3,5(2H,4H)-二酮类似物的结构-活性关系研究：开发针对三阴性乳腺癌的有效 eEF2K 降解剂

eEF2K 是一种非典型 α 激酶，负责调节蛋白质合成和能量稳态。 eEF2K 功能异常与多种人类癌症有关，包括三阴性乳腺癌 (TNBC)。然而，当前 eEF2K 调节剂的细胞活性有限阻碍了其临床应用。基于我们的命中I4和C1的 2-苯基-1,2,4-三嗪-3,5(2 H ,4 H )-二酮支架，构效关系分析发现了几种更具活性的衍生物（例如， 19、34和36 )抑制TNBC细胞系MDA-MB- 231的生存力。此外，最有效的化合物36显着抑制 MDA-MB-231 和 HCC1806 细胞系的活力、增殖和迁移。从机制上讲，化合物36对 eEF2K 蛋白具有高结合亲和力，并有效诱导其降解。此外，在MDA-MB-231细胞异种移植小鼠模型中， 36发挥了与紫杉醇相当的肿瘤抑制作用，且没有明显毒性，表明化合物36可以开发为TNBC治疗的潜在新型疗法。

更新日期：2024-08-29

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