Structure–Activity\nRelationship Studies of\nSubstituted 2‑Phenyl-1,2,4-triazine-3,5(2<i>H</i>,4<i>H</i>)‑dione Analogues: Development of Potent\neEF2K Degraders against Triple-Negative Breast Cancer

eEF2K, an atypical alpha-kinase, is responsible for regulating\nprotein synthesis and energy homeostasis. Aberrant eEF2K function\nhas been linked to various human cancers, including triple-negative\nbreast cancer (TNBC). However, limited cellular activity of current\neEF2K modulators impedes their clinical application. Based on the\n2-phenyl-1,2,4-triazine-3,5(2<i>H</i>,4<i>H</i>)-dione scaffold of our hits <b>I4</b> and <b>C1</b>,\nstructure–activity relationship analysis led to the discovery\nof several more active derivatives (e.g., <b>19</b>, <b>34</b>, and <b>36</b>) in inhibiting the viability of TNBC cell line\nMDA-MB-231. Moreover, the most potent compound <b>36</b> significantly\nsuppresses the viability, proliferation, and migration of both MDA-MB-231\nand HCC1806 cell lines. Mechanistically, compound <b>36</b> has\na high binding affinity for the eEF2K protein and effectively induces\nits degradation. Additionally, <b>36</b> exerts a comparable\ntumor-suppressive effect to paclitaxel in an MDA-MB-231 cell xenograft\nmouse model with no obvious toxicity, demonstrating that compound <b>36</b> could be developed as a potential novel therapeutic for\nTNBC treatment.