2. Academic Validation
  3. Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε

Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε

  • J Med Chem. 2025 Jan 9;68(1):506-530. doi: 10.1021/acs.jmedchem.4c02201.
Adrian Haag 1 2,  Václav Němec 1 2,  Pavlína Janovská 3,  Jana Bartošíková 3,  Bikash Adhikari 4,  Juliane Müller 4,  Martin P Schwalm 1 2,  Štěpán Čada 3,  Uli Ohmayer 5,  Henrik Daub 5,  Yeojin Kim 1 2,  Florian Born 1 2,  Elmar Wolf 4,  Vítězslav Bryja 3,  Stefan Knapp 1 2 6
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 2 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 3 Department of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic.
  • 4 Institute of Biochemistry, University of Kiel, Rudolf-Höber-Str. 1, Kiel 24118, Germany.
  • 5 NEOsphere Biotechnologies GmbH, Fraunhoferstr. 1, 82152 Martinsried, Germany.
  • 6 German translational cancer network (DKTK) site Frankfurt Mainz, 60590 Heidelberg, Germany.
PMID: 39729064 DOI: 10.1021/acs.jmedchem.4c02201
Abstract

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 CK1δ and CK1ε with excellent selectivity over the highly related CK1α isoform. The developed PROTAC, AH078 (37) selectively degraded CK1δ and CK1ε 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 CK1δ and CK1ε function in cellular systems.

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