丝裂原激活蛋白激酶激活蛋白激酶 2 (MK2) 成为开发抗癌疗法的关键靶点。由于效力和选择性不足，ATP 竞争性抑制剂的局限性凸显了对共价不可逆 MK2 抑制剂的迫切需要。我们对癌症基因组图谱数据库的初步分析显示，MK2 在各种癌症类型中过度表达，尤其是那些以炎症为特征的癌症，将其与不良预后联系起来并强调了其重要性。通过研究 MK2 的激酶结构域，鉴定出了一个独特的半胱氨酸残基，从而能够创建靶向共价抑制剂。化合物 11 的开发显示出强大的 MK2 抑制作用 (IC50 = 2.3 nM) 和高选择性。它不可逆地与 MK2 结合，实现长时间的信号抑制并减少巨噬细胞中的病理性炎症细胞因子。此外，化合物11或MK2敲低可以在体外和体内抑制促肿瘤巨噬细胞M2表型。在富含巨噬细胞的肿瘤模型中，化合物 11 以剂量依赖性方式显着减缓生长。这些发现支持 MK2 作为一种有前途的抗癌靶点，尤其与炎症引发或巨噬细胞主导的癌症相关，并提供化合物 11 作为探索 MK2 功能的宝贵化学工具。© 2024 作者。四川国际医学交流中心出版的MedComm

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) emerges as a pivotal target in developing anti-cancer therapies. The limitations of ATP-competitive inhibitors, due to insufficient potency and selectivity, underscore the urgent need for a covalent irreversible MK2 inhibitor. Our initial analyses of The Cancer Genome Atlas database revealed MK2's overexpression across various cancer types, especially those characterized by inflammation, linking it to poor prognosis and highlighting its significance. Investigating MK2's kinase domain led to the identification of a unique cysteine residue, enabling the creation of targeted covalent inhibitors. Compound 11 was developed, demonstrating robust MK2 inhibition (IC50 = 2.3 nM) and high selectivity. It binds irreversibly to MK2, achieving prolonged signal suppression and reducing pathological inflammatory cytokines in macrophages. Furthermore, compound 11 or MK2 knockdown can inhibit the tumor-promoting macrophage M2 phenotype in vitro and in vivo. In macrophage-rich tumor model, compound 11 notably slowed growth in a dose-dependent manner. These findings support MK2 as a promising anticancer target, especially relevant in cancers fueled by inflammation or dominated by macrophages, and provide compound 11 serving as an invaluable chemical tool for exploring MK2's functions.© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.