Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK.
The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC50CK1δ = 4 nM, IC50CK1ε = 25 nM), 12a (IC50CK1δ = 19 nM, IC50CK1ε = 227 nM), and 16b (IC50CK1δ = 8 nM, IC50CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50= 3.5 µM) and Panc89 (EC50= 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of16bin CK1δ and11bin p38α.
Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24118 Kiel, Germany. jhalekotte@pharmazie.uni-kiel.de.
Jakob
J
Halekotte
Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24118 Kiel, Germany. lwitt@pharmazie.uni-kiel.de.
Lydia
L
Witt
Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. chiara.ianes@uni-ulm.de.
Chiara
C
Ianes
Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. marcm3012@googlemail.com.
Marc
M
Krüger
Institute of Chemical Biology, Dortmund University of Technology, Otto-Hahn-Straße 4a, D-44227 Dortmund, Germany. uwe.knippschild@uniklinik-ulm.de.
Mike
M
Bührmann
Institute of Chemical Biology, Dortmund University of Technology, Otto-Hahn-Straße 4a, D-44227 Dortmund, Germany. mike.buehrmann@googlemail.com.
Daniel
D
Rauh
Department for Chemistry, University of Cologne, Otto-Fischer-Straße 12-14, D-50674 Cologne, Germany. daniel.rauh@tu-dortmund.de.
Christian
C
Pichlo
Department for Chemistry, University of Cologne, Otto-Fischer-Straße 12-14, D-50674 Cologne, Germany. pichloc@uni-koeln.de.
Elena
E
Brunstein
The Ferrier Research Institute, Victoria University of Wellington, Gracefield Research Centre, 69 Gracefield Road, Lower Hutt P.O. Box 33-436, New Zealand. Elena.Brunstein@uni-koeln.de.
Andreas
A
Luxenburger
Department for Chemistry, University of Cologne, Otto-Fischer-Straße 12-14, D-50674 Cologne, Germany. ubaumann@uni-koeln.de.
Ulrich
U
Baumann
Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. Andreas.Luxenburger@vuw.ac.nz.
Uwe
U
Knippschild
Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, Germany. joachim.bischof@uniklinik-ulm.de.
Joachim
J
Bischof
Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24118 Kiel, Germany. cpeifer@pharmazie.uni-kiel.de.
Christian
C
Peifer
D000255:Adenosine Triphosphate / Q000494:pharmacology; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry*; D008958:Models, Molecular; D010802:Phylogeny; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D048148:Casein Kinase Idelta; D048308:Mitogen-Activated Protein Kinase 14
4,5-diaryl-imidazoles; Alzheimer’s disease; amyotrophic lateral sclerosis; cancer; familial advanced sleep phase syndrome; formerly known as casein kinase 1; kinase inhibitors; p38 MAPK; protein kinase CK1