| Autor: |
Zhao X; Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Zhong C; Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China., Zhu R; Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Gong R; Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China., Liu B; Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., He L; Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China., Tian S; Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.; Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou 215123, China., Jin J; Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Jiang T; Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China., Chen JL; Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Wan X; Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China., Liu W; Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Jiang S; Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410011, China., Deng P; Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China., Cheng Y; Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China.; Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China., Ye N; Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.; Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou 215123, China. |
| Abstrakt: |
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(2 H ,4 H )-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. |
