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

Mingfeng Yu; Peng Li; Sunita K C Basnet; Malika Kumarasiri; Sarah Diab; Theodosia Teo; Hugo Albrecht; Shudong Wang

doi:10.1016/j.ejmech.2015.03.032

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

Eur J Med Chem. 2015 May 5:95:116-26. doi: 10.1016/j.ejmech.2015.03.032. Epub 2015 Mar 17.

Authors

Mingfeng Yu¹, Peng Li¹, Sunita K C Basnet¹, Malika Kumarasiri¹, Sarah Diab¹, Theodosia Teo¹, Hugo Albrecht¹, Shudong Wang²

Affiliations

¹ 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.
² 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.

PMID: 25800647
DOI: 10.1016/j.ejmech.2015.03.032

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.

Keywords: Inhibitor; Mnk; Structure–activity relationship; Thieno[2,3-d]pyrimidine derivatives; eIF4E.

Publication types

Evaluation Study
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Apoptosis / drug effects
Carboxylic Acids / chemical synthesis*
Carboxylic Acids / pharmacology*
Cell Cycle / drug effects
Cell Proliferation / drug effects
Drug Discovery*
Eukaryotic Initiation Factor-4E / metabolism
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / enzymology
Leukemia, Myeloid, Acute / pathology
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacology*
Structure-Activity Relationship
Thiophenes / chemical synthesis*
Thiophenes / pharmacology*
Tumor Cells, Cultured

Substances

4-((1,5-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-5-methylthieno(2,3-d)pyrimidine-6-carboxylic acid
4-((1-(2-Methoxyethyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-5-methylthieno(2,3-d)pyrimidine-6-carboxamide
Carboxylic Acids
Eukaryotic Initiation Factor-4E
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Pyrimidines
Thiophenes
Adenosine Triphosphate
MKNK1 protein, human
Protein Serine-Threonine Kinases