Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity

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Abstract: Casein kinases 1 (CK1) are key signaling molecules that have emerged recently as attractive therapeutic targets in particular for the treatment of hematological malignancies. Herein, we report the identification of a new class of potent and highly selective inhibitors of CK1α, δ and ϵ. Based on their optimal in vitro and in vivo profiles and their exclusive selectivity, MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms. At proper concentrations, MU1250 and MU1500 allow for specific targeting of CK1δ or dual inhibition of CK1δ/ϵ in cells. The compound MU1742 also efficiently inhibits CK1α and, to our knowledge, represents the first potent and highly selective inhibitor of this enzyme. In addition, we demonstrate that the central 1H-pyrrolo[2,3-b]pyridine-imidazole pharmacophore can be used as the basis of highly selective inhibitors of other therapeutically relevant protein kinases, e.g. p38α, as exemplified by the compound MU1299.

Newly identified chemical biology probes MU1250, MU1500, and MU1742, based on the 1H-pyrrolo[2,3-b]pyridine-imidazole scaffold, allow for highly specific targeting of the isoforms CK1α, CK1δ, and CK1ϵ in cells as well as in vivo. Our observations suggest that the central scaffold can be used more broadly in compounds targeting other protein kinases, as evidenced by the highly selective p38α inhibitor MU1299.


Václav Němec 1,2, Prashant Khirsariya 1,2, Pavlína Janovská 3, Paula Martín Moyano 1, Lukáš Maier 1,2, Petra Procházková 3, Pavlína Kebková 3, Tomáš Gybel’ 3, Benedict-Tilman Berger 4, Apirat Chaikuad 4, Maria Reinecke 5, Bernhard Kuster 5,6, Stefan Knapp 4, Vítězslav Bryja 3, Kamil Paruch 1,2

  • 1 Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
  • 2 International Clinical Research Centre, St. Anne’s University Hospital, Pekařská 53, Brno, 656 91, Czech Republic.
  • 3 Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
  • 4 Institute for Pharmaceutical Chemistry, Structural Genomics Consortium, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 15, 60438, Frankfurt am Main, Germany.
  • 5 Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, 85354, Freising, Germany.
  • 6 Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technical University of Munich, 85354, Freising, Germany.