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 (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.