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

Ramakrishna Edupuganti; Qiantao Wang; Clint D J Tavares; Catrina A Chitjian; James L Bachman; Pengyu Ren; Eric V Anslyn; Kevin N Dalby

doi:10.1016/j.bmc.2014.06.050

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

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

Authors

Ramakrishna Edupuganti¹, Qiantao Wang², Clint D J Tavares³, Catrina A Chitjian³, James L Bachman⁴, Pengyu Ren⁵, Eric V Anslyn⁶, Kevin N Dalby⁷

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Dose-Response Relationship, Drug
Elongation Factor 2 Kinase / antagonists & inhibitors*
Elongation Factor 2 Kinase / metabolism
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Recombinant Proteins / metabolism
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Protein Kinase Inhibitors
Pyridines
Pyrimidinones
Recombinant Proteins
EEF2K protein, human
Elongation Factor 2 Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding