Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε
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 (<b>37</b>) targeting CK1δ and CK1ε with excellent selectivity over the highly related CK1α isoform. The developed PROTAC, AH078 (<b>37</b>) selectively degraded CK1δ and CK1ε with a DC<sub>50</sub> of 200 nM. Characterization of AH078 (<b>37</b>) revealed a VHL and Ubiquitin-dependent degradation mechanism. Thus, AH078 (<b>37</b>) represents a versatile chemical tool to study CK1δ and CK1ε function in cellular systems.
Authors
- Bikash Adhikari (ORCID: https://orcid.org/0000-0002-9064-0356)
- Stefan Knapp (ORCID: https://orcid.org/0000-0001-5995-6494)
- Pavlína Janovská (ORCID: https://orcid.org/0000-0001-9871-0876)
- Václav Němec (ORCID: https://orcid.org/0000-0001-6900-1368)
- Martin P. Schwalm (ORCID: https://orcid.org/0000-0002-1252-1829)
- Henrik Daub
- Yeojin Kim (ORCID: https://orcid.org/0009-0009-2647-7046)
- Jana Bartošíková (ORCID: https://orcid.org/0000-0002-2732-3681)
- Štěpán Čada (ORCID: https://orcid.org/0000-0003-1517-5631)
- Vı́tězslav Bryja (ORCID: https://orcid.org/0000-0002-9136-5085)
- Uli Ohmayer (ORCID: https://orcid.org/0000-0003-0438-0410)
- Elmar Wolf (ORCID: https://orcid.org/0000-0002-5299-6335)
- Juliane Müller (ORCID: https://orcid.org/0000-0003-2126-6521)
- Annemarie Haag
- Florian Born
Institutions
- Goethe University Frankfurt (DE)
- Masaryk University (CZ)
- Christian-Albrechts-Universität zu Kiel (DE)
- Institute of Experimental Physics of the Slovak Academy of Sciences (SK)
- Frankfurt Cancer Institute (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02201
- Citations
- 3
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 0.85
Funders
- Deutsches Krebsforschungszentrum
- Innovative Health Initiative
- Deutsche Forschungsgemeinschaft
- Grantová Agentura České Republiky
- Deutsche Krebshilfe
- European Research Council