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Bioorg Med Chem. 2014 Sep 1;22(17):4910-6. doi: 10.1016/j.bmc.2014.06.050. Epub 2014 Jun 30.

Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors.

Author information

1
Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, TX 78712, USA; Department of Chemistry, The University of Texas at Austin, TX 78712, USA.
2
Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, TX 78712, USA; Department of Biomedical Engineering, Cockrell School of Engineering, College of Engineering, The University of Texas at Austin, TX 78712, USA.
3
Graduate Program in Cell and Molecular Biology, The University of Texas at Austin, TX 78712, USA.
4
Department of Chemistry, The University of Texas at Austin, TX 78712, USA.
5
Department of Biomedical Engineering, Cockrell School of Engineering, College of Engineering, The University of Texas at Austin, TX 78712, USA.
6
Department of Chemistry, The University of Texas at Austin, TX 78712, USA. Electronic address: anslyn@austin.utexas.edu.
7
Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, TX 78712, USA; Graduate Program in Cell and Molecular Biology, The University of Texas at Austin, TX 78712, USA. Electronic address: dalby@austin.utexas.edu.

Abstract

A small molecule library of pyrido[2,3-d]pyrimidine-2,4-dione derivatives 6-16 was synthesized from 6-amino-1,3-disubstituted uracils 18, characterized, and screened for inhibitory activity against eukaryotic elongation factor-2 kinase (eEF-2K). To understand the binding pocket of eEF-2K, structural modifications of the pyrido[2,3-d]pyrimidine were made at three regions (R(1), R(2), and R(3)). A homology model of eEF-2K was created, and compound 6 (A-484954, Abbott laboratories) was docked in the catalytic domain of eEF-2K. Compounds 6 (IC50=420nM) and 9 (IC50=930nM) are found to be better molecules in this preliminary series of pyrido[2,3-d]pyrimidine analogs. eEF-2K activity in MDA-MB-231 breast cancer cells is significantly reduced by compound 6, to a lesser extent by compound 9, and is unaffected by compound 12. Similar inhibitory results are observed when eEF-2K activity is stimulated by 2-deoxy-d-glucose (2-DOG) treatment, suggesting that compounds 6 and 9 are able to inhibit AMPK-mediated activation of eEF-2K to a notable extent. The results of this work will shed light on the further design and optimization of novel pyrido[2,3-d]pyrimidine analogs as eEF-2K inhibitors.

KEYWORDS:

Homology modeling; Kinase inhibitor; Pyrido[2,3-d]pyrimidine-2,4-dione; Uracil; eEF-2K inhibitor

PMID:
25047940
PMCID:
PMC6473179
DOI:
10.1016/j.bmc.2014.06.050
[Indexed for MEDLINE]
Free PMC Article

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