Focused screening to identify new adenosine kinase inhibitors.
Adenosine kinase (AdK) is a key player in controlling intra- and extracellular concentrations of the signaling molecule adenosine. Extensive evidence points to an important role of AdK in several diseases, and suggests that AdK inhibition might be a promising therapeutic strategy. The development of a new AdK assay and subsequent screening of part of our focused compound library led to the identification of 12 hit compounds (hit rate of 6%) representing six new classes of non-nucleoside human AdK inhibitors. The most potent inhibitor 1 displayed a Kivalue of 184nM. Compound screening with a newly developed assay was useful and efficient for discovering novel AdK inhibitors which may serve as lead structures for developing drugs for adenosine augmentation therapy.
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: mkoese@uni-bonn.de.
Meryem
M
Köse
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Anke C
AC
Schiedel
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Alexander Andreas
AA
Bauer
Department Pharmazie, Zentrum für Pharmaforschung, Universität München, Butenandtstr. 7, D-81377 München, Germany.
Hermann
H
Poschenrieder
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Joachim C
JC
Burbiel
University College of Pharmaceutical Sciences, Kakatiya University, Warangal, A.P. 506009, India.
Raghuram Rao
RR
Akkinepally
Department Pharmazie, Zentrum für Pharmaforschung, Universität München, Butenandtstr. 7, D-81377 München, Germany.
Hans-Dietrich
HD
Stachel
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Christa E
CE
Müller
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D000248:Adenosine Kinase
Adenosine homeostasis; Adenosine kinase assay; Adenosine kinase inhibitors; Compound library; High-throughput screening