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.

Department of Experimental Biology Faculty of Science Masaryk University 625 00 Brno Czech Republic

German translational cancer network site Frankfurt Mainz 60590 Heidelberg Germany

Institute of Biochemistry University of Kiel Rudolf Höber Str 1 Kiel 24118 Germany

Institute of Pharmaceutical Chemistry Goethe University Max von Laue Str 9 60438 Frankfurt am Main Germany

NEOsphere Biotechnologies GmbH Fraunhoferstr 1 82152 Martinsried Germany

Structural Genomics Consortium Buchmann Institute for Life Sciences Max von Laue Str 15 60438 Frankfurt am Main Germany

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