Remodeling tumor‐associated macrophage for anti‐cancer effects by rational design of irreversible inhibition of mitogen‐activated protein kinase‐activated protein kinase 2
Danyi Wang,
Deqiao Sun,
Xiaoyan Wang,
Xia Peng,
Yinchun Ji,
Lu Tang,
Qichang He,
Danqi Chen,
Ye Yang,
Xuan Zhou,
Bing Xiong,
Jing Ai
Affiliations
Danyi Wang
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai P. R. China
Deqiao Sun
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai P. R. China
Xiaoyan Wang
School of PharmacyUniversity of Chinese Academy of SciencesBeijing P. R. China
Xia Peng
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai P. R. China
Yinchun Ji
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai P. R. China
Lu Tang
School of PharmacyUniversity of Chinese Academy of SciencesBeijing P. R. China
Qichang He
State Key Laboratory of Chemical Biology Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai P. R. China
Danqi Chen
School of PharmacyUniversity of Chinese Academy of SciencesBeijing P. R. China
Ye Yang
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai P. R. China
Xuan Zhou
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai P. R. China
Bing Xiong
School of PharmacyUniversity of Chinese Academy of SciencesBeijing P. R. China
Jing Ai
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai P. R. China
Abstract 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.
