title: 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.
abstract: 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.
authors: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Center for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors: Mingfeng
authors: M
authors: Yu
authors: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Center for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors: Peng
authors: P
authors: Li
authors: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Center for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors: Sunita K C
authors: SK
authors: Basnet
authors: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Center for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors: Malika
authors: M
authors: Kumarasiri
authors: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Center for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors: Sarah
authors: S
authors: Diab
authors: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Center for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors: Theodosia
authors: T
authors: Teo
authors: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Center for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
authors: Hugo
authors: H
authors: Albrecht
authors: Centre for Drug Discovery and Development, Sansom Institute for Health Research and Center for Cancer Biology, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia. Electronic address: shudong.wang@unisa.edu.au.
authors: Shudong
authors: S
authors: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C000604658:4-((1,5-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-5-methylthieno(2,3-d)pyrimidine-6-carboxylic acid; C000604656:4-((1-(2-Methoxyethyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-5-methylthieno(2,3-d)pyrimidine-6-carboxamide; D002264:Carboxylic Acids; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D000255:Adenosine Triphosphate; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Inhibitor; Mnk; Structure–activity relationship; Thieno[2,3-d]pyrimidine derivatives; eIF4E