Optimized 4,5-diarylimidazoles as potent/selective inhibitors of Protein Kinase CK1δ and their structural relation to P38α MAPK

Jakob Halekotte, Lydia Witt, Chiara Ianes, Marc Krüger, Mike Bührmann, Daniel Rauh, Christian Pichlo, Elena Brunstein, Andreas Luxenburger, Ulrich Baumann, Uwe Knippschild, Joachim Bischof, Christian Peifer, Pierre Koch, Stefan Laufer

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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 (IC50 CK1δ = 4 nM, IC50 CK1ϵ = 25 nM), 12a (IC50 CK1δ = 19 nM, IC50 CK1ϵ = 227 nM), and 16b (IC50 CK1δ = 8 nM, IC50 CK1ϵ = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound 11b, 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 of 16b in CK1δ and 11b in p38α.

Original languageEnglish
Article number522
Issue number4
StatePublished - Apr 2017
Externally publishedYes


  • 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


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