title: Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors.
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.
authors.affiliation: 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.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Edupuganti
authors.affiliation: 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.
authors.forename: Qiantao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Graduate Program in Cell and Molecular Biology, The University of Texas at Austin, TX 78712, USA.
authors.forename: Clint D J
authors.initials: CD
authors.lastname: Tavares
authors.affiliation: Graduate Program in Cell and Molecular Biology, The University of Texas at Austin, TX 78712, USA.
authors.forename: Catrina A
authors.initials: CA
authors.lastname: Chitjian
authors.affiliation: Department of Chemistry, The University of Texas at Austin, TX 78712, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Bachman
authors.affiliation: Department of Biomedical Engineering, Cockrell School of Engineering, College of Engineering, The University of Texas at Austin, TX 78712, USA.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Ren
authors.affiliation: Department of Chemistry, The University of Texas at Austin, TX 78712, USA. Electronic address: anslyn@austin.utexas.edu.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Anslyn
authors.affiliation: 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.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
mesh_terms: D004305:Dose-Response Relationship, Drug; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011744:Pyrimidinones; D011994:Recombinant Proteins; C517689:EEF2K protein, human; D054736:Elongation Factor 2 Kinase
keywords: Homology modeling; Kinase inhibitor; Pyrido[2,3-d]pyrimidine-2,4-dione; Uracil; eEF-2K inhibitor