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

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

  • J Med Chem. 2024 Sep 12;67(17):15837-15861. 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
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • 2 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
  • 3 Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha 410011, China.
  • 4 Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou 215123, China.
  • 5 Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410011, China.
  • 6 Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China.
PMID: 39208364 DOI: 10.1021/acs.jmedchem.4c01484
Abstract

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.

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