Discovery of 4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3-d]pyrimidine derivatives as potent Mnk inhibitors: synthesis, structure-activity relationship analysis and biological evaluation.
Phosphorylation of the eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is essential for oncogenesis but unnecessary for normal development. Thus, pharmacological inhibition of Mnks may offer an effective and non-toxic anti-cancer therapeutic strategy. Herein, we report the discovery of 4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3-d]pyrimidine derivatives as potent Mnk inhibitors. Docking study of 7a in Mnk2 suggests that the compound is stabilised in the ATP binding site through multiple hydrogen bonds and hydrophobic interaction. Cellular mechanistic studies on MV-4-11 cells with leads 7a, 8e and 8f reveal that they are able to down-regulate the phosphorylated eIF4E, Mcl-1 and cyclin D1, and induce apoptosis.
['Yu|Mingfeng|M|', 'Li|Peng|P|', 'Basnet|Sunita K C|SK|', 'Kumarasiri|Malika|M|', 'Diab|Sarah|S|', 'Teo|Theodosia|T|', 'Albrecht|Hugo|H|', 'Wang|Shudong|S|']
D000255:Adenosine Triphosphate D017209:Apoptosis D002264:Carboxylic Acids D002453:Cell Cycle D049109:Cell Proliferation D055808:Drug Discovery D039561:Eukaryotic Initiation Factor-4E D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D015470:Leukemia, Myeloid, Acute D010766:Phosphorylation D047428:Protein Kinase Inhibitors D017346:Protein Serine-Threonine Kinases D011743:Pyrimidines D013329:Structure-Activity Relationship D013876:Thiophenes D014407:Tumor Cells, Cultured
Mnk Inhibitor eIF4E Structure–activity relationship Thieno[2,3-d]pyrimidine derivatives