Development and\nDiscovery of a Selective Degrader\nof Casein Kinases 1 δ/ε

Members\nof the casein kinase 1 (CK1) family have emerged as key\nregulators of cellular signaling and as potential drug targets. Functional\nannotation of the 7 human isoforms would benefit from isoform-selective\ninhibitors, allowing studies on the role of these enzymes in normal\nphysiology and disease pathogenesis. However, due to significant sequence\nhomology within the catalytic domain, isoform selectivity is difficult\nto achieve with conventional small molecules. Here, we used a PROTAC\n(Proteolysis TArgeting Chimeras) approach to develop a highly selective\ndegrader AH078 (<b>37</b>) targeting CK1δ and CK1ε\nwith excellent selectivity over the highly related CK1α isoform.\nThe developed PROTAC, AH078 (<b>37</b>) selectively degraded\nCK1δ and CK1ε with a DC<sub>50</sub> of 200 nM. Characterization\nof AH078 (<b>37</b>) revealed a VHL and Ubiquitin-dependent\ndegradation mechanism. Thus, AH078 (<b>37</b>) represents a\nversatile chemical tool to study CK1δ and CK1ε function\nin cellular systems.