Discovery of 5-( 2-( Phenylamino) pyrimidin-4-yl) thiazol2( 3H)- one Derivatives as Potent Mnk2 Inhibitors: Synthesis, SAR Analysis and Biological Evaluation

作者：Diab Sarah^*; Teo Theodosia; Kumarasiri Malika; Li Peng; Yu Mingfeng; Lam Frankie; Basnet Sunita K C; Sykes Matthew J; Albrecht Hugo; Milne Robert; Wang Shudong

来源：ChemMedChem, 2014, 9(5): 962-972.

DOI：10.1002/cmdc.201300552

• anticancer drug discovery
• apoptosis
• CGP57380
• eIF4E phosphorylation
• Mnk inhibitors

Phosphorylation of eIF4E by human mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is crucial for human tumourigenesis and development. Targeting Mnks may provide a novel anticancer therapeutic strategy. However, the lack of selective Mnk inhibitors has so far hampered pharmacological target validation and clinical drug development. Herein, we report, for the first time, the discovery of a series of 5-(2-(phenylamino)pyrimidin-4-yl)thiazole-2(3H)-one derivatives as Mnk inhibitors. Several derivatives demonstrate very potent Mnk2 inhibitory activity. The most active and selective compounds were tested against a panel of cancer cell lines, and the results confirm the cell-type-specific effect of these Mnk inhibitors. Detailed cellular mechanistic studies reveal that Mnk inhibitors are capable of reducing the expression level of anti-apoptotic protein Mcl-1, and of promoting apoptosis in MV4-11 acute myeloid leukaemia cells.

• 出版日期2014-5