Structure-Based Development of Isoform-Selective Inhibitors of Casein Kinase 1ε vs Casein Kinase 1δ

Specific inhibition of a single kinase isoform is a challenging
task due to the highly conserved nature of ATP-binding sites. Casein
kinase 1 (CK1) δ and ε share 97% sequence identity in
their catalytic domains. From a comparison of the X-ray crystal structures
of CK1δ and CK1ε, we developed a potent and highly CK1ε-isoform-selective
inhibitor (SR-4133). The X-ray co-crystal structure of the CK1δ−SR-4133
complex reveals that the electrostatic surface between the naphthyl
unit of SR-4133 and CK1δ is mismatched, destabilizing the interaction
of SR-4133 with CK1δ. Conversely, the hydrophobic surface area
resulting from the Asp−Phe−Gly motif (DFG)-out conformation
of CK1ε stabilizes the binding of SR-4133 in the ATP-binding
pocket of CK1ε, leading to the selective inhibition of CK1ε.
The potent CK1ε-selective agents display nanomolar growth inhibition
of bladder cancer cells and inhibit the phosphorylation of 4E-BP1
in T24 cells, which is a direct downstream effector of CK1ε.