Eukaryotic elongation factor 2 kinase (eEF2K), a member of the atypical ?-kinase family, is highly expressed in a variety of tumor tissues. Inhibition of eEF2K function can effectively kill cancer cells without affecting the function of normal cells. Therefore, eEF2K is a promising new target for cancer therapy. In this study, a series of benzamide tryptamine derivatives were designed and synthesized as novel eEF2K inhibitors. The druggability properties of the synthesized compounds were predicted in silico and performed well. The MTT assay indicated that most of these compounds displayed good antiproliferative activity against human leukemia CCRF-CEM and K562 cell lines. The structure?activity relationship (SAR) revealed that substituents with different electronic effects on the C5 position of indole ring or C2?, C4? positions of benzene ring have a great influence on the anti-proliferative activity. Among them, 5j demonstrated the highest anti-proliferative activity with IC50 value of 1.63?3.54??M. this compound displayed an effective eEF2K inhibition by down-regulated the level of phosphorylated eEF2 in CCRF-CEM cells. Additionally, the western blot analysis further revealed that 5j also significantly affected eEF2K-related signaling pathways. Anticancer mechanism studies have shown that 5j arrested the cell cycle in G0/G1 and induced CCRF-CEM cells apoptosis. Furthermore, 5j activated cleaved caspase-9, 8, 3 and cleaved PARP in a time-dependent manner, which suggesting that 5j induced cancer cells apoptosis through both intrinsic and extrinsic pathways. In summary, benzamide tryptamine derivative 5j represents a novel and promising lead structure for the development of eEF2K inhibitors in cancer therapy.

» Author: Zedong Liu, Aili Jiang, Yaqi Wang, Pei Xu, Qiting Zhang, Yinda Wang, Shan He, Ning Wang, Haixiao Jin, Bin Zhang

» Publication Date: 01/07/2022

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