Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε
| Authors | |
|---|---|
| Year of publication | 2025 |
| Type | Article in Periodical |
| Magazine / Source | Journal of Medicinal Chemistry |
| MU Faculty or unit | |
| Citation | |
| web | https://doi.org/10.1021/acs.jmedchem.4c02201 |
| Doi | http://dx.doi.org/10.1021/acs.jmedchem.4c02201 |
| Keywords | Assays; Degradation; Inhibitors; Mixtures; Peptides and proteins |
| Description | Members of the casein kinase 1 (CK1) family have emerged as key regulators of cellular signaling and as potential drug targets. Functional annotation of the 7 human isoforms would benefit from isoform-selective inhibitors, allowing studies on the role of these enzymes in normal physiology and disease pathogenesis. However, due to significant sequence homology within the catalytic domain, isoform selectivity is difficult to achieve with conventional small molecules. Here, we used a PROTAC (Proteolysis TArgeting Chimeras) approach to develop a highly selective degrader AH078 (37) targeting CK1 delta and CK1 epsilon with excellent selectivity over the highly related CK1 alpha isoform. The developed PROTAC, AH078 (37) selectively degraded CK1 delta and CK1 epsilon with a DC50 of 200 nM. Characterization of AH078 (37) revealed a VHL and Ubiquitin-dependent degradation mechanism. Thus, AH078 (37) represents a versatile chemical tool to study CK1 delta and CK1 epsilon function in cellular systems. |
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