Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity
| Authors | |
|---|---|
| Year of publication | 2023 |
| Type | Article in Periodical |
| Magazine / Source | Angewandte Chemie International Edition |
| MU Faculty or unit | |
| Citation | |
| Web | https://doi.org/10.1002/anie.202217532 |
| Doi | http://dx.doi.org/10.1002/anie.202217532 |
| Keywords | CK1; Chemical Probe; Inhibitor; Isoform Selectivity; Wnt Pathway |
| Description | 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 CK1?, ? and ?. 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 CK1? or dual inhibition of CK1?/? in cells. The compound MU1742 also efficiently inhibits CK1? 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. p38?, as exemplified by the compound MU1299. |
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