2. Academic Validation
  3. 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

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.
Mingfeng Yu 1,  Peng Li 1,  Sunita K C Basnet 1,  Malika Kumarasiri 1,  Sarah Diab 1,  Theodosia Teo 1,  Hugo Albrecht 1,  Shudong Wang 2
Affiliations

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.

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