EIF4E公司
第1周
化学
激酶
癌症研究
磷酸化
伊布替尼
真核起始因子
夏普
淋巴瘤
细胞周期
细胞生物学
细胞凋亡
翻译(生物学)
细胞周期蛋白依赖激酶1
生物化学
生物
白血病
免疫学
慢性淋巴细胞白血病
程序性细胞死亡
信使核糖核酸
基因
半胱氨酸蛋白酶
作者
Xinrui Yuan,Dezhong Guan,Chao Chen,Shanshan Guo,Hailing Wu,Hong Bu,Chao‐Yie Yang,M Wang,Jinpei Zhou,Huibin Zhang
标识
DOI:10.1021/acs.jmedchem.3c02008
摘要
The mitogen-activated protein kinase-interacting protein kinases (MNKs) are the only kinases known to phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at Ser209, which plays a significant role in cap-dependent translation. Dysregulation of the MNK/eIF4E axis has been found in various solid tumors and hematological malignancies, including diffuse large B-cell lymphoma (DLBCL). Herein, structure-activity relationship studies and docking models determined that 20j exhibits excellent MNK1/2 inhibitory activity, stability, and hERG safety. 20j exhibits strong and broad antiproliferative activity against different cancer cell lines, especially GCB-DLBCL DOHH2. 20j suppresses the phosphorylation of eIF4E in Hela cells (IC50 = 90.5 nM) and downregulates the phosphorylation of eIF4E and 4E-BP1 in A549 cells. In vivo studies first revealed that ibrutinib enhances the antitumor effect of 20j without side effects in a DOHH2 xenograft model. This study provided a solid foundation for the future development of a MNK inhibitor for GCB-DLBCL treatment.
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