State Key Laboratory of Biotherapy and Cancer Center and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
J Med Chem. 2021 Jul 8;64(13):8870-8883. doi: 10.1021/acs.jmedchem.0c02218. Epub 2021 Jun 23.
Eukaryotic elongation factor 2 kinase (eEF2K), a member of the atypical protein kinase family of alpha-kinases, is well-known as a negative regulator of protein synthesis by phosphorylating eEF2. Notably, eEF2K functions as a key regulator of several cellular processes, leading to tumorigenesis. To date, some small-molecule compounds have been reported as potential eEF2K inhibitors in cancer drug discovery. However, an ideal targeted drug design still faces huge challenges. Alternatively, other design strategies, such as repurposed drugs, dual-target drugs, and drug combination strategies, provide insights into the improvement of cancer treatment. Here, we summarize the crucial eEF2K-modulating pathways in cancer, including AMPK, REDD1, and Src. Moreover, we discuss the inhibition of eEF2K with single-target inhibitors, repurposed drugs, dual-target inhibitors, drug combination strategies, and other emerging technologies for therapeutic purposes. Together, these inspiring findings provide insights into a promising strategy for inhibiting eEF2K with small-molecule compounds to improve potential cancer therapy.
真核延伸因子 2 激酶（eEF2K）是一种非典型蛋白激酶家族的α-激酶成员，通过磷酸化 eEF2 而成为蛋白质合成的负调节剂而广为人知。值得注意的是，eEF2K 作为几个细胞过程的关键调节剂，导致了肿瘤的发生。迄今为止，一些小分子化合物已被报道为癌症药物发现中潜在的 eEF2K 抑制剂。然而，理想的靶向药物设计仍然面临巨大的挑战。或者，其他设计策略，如重新利用药物、双靶药物和药物联合策略，为改善癌症治疗提供了思路。在这里，我们总结了癌症中关键的 eEF2K 调节途径，包括 AMPK、REDD1 和 Src。此外，我们还讨论了用单靶抑制剂、再利用药物、双靶抑制剂、药物联合策略和其他新兴技术抑制 eEF2K 以达到治疗目的。总之，这些鼓舞人心的发现为用小分子化合物抑制 eEF2K 以改善潜在的癌症治疗提供了一个有前途的策略。
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