The protein kinase CK1: Inhibition, activation, and possible allosteric modulation

Protein kinases play a vital role in biology and deregulation of kinases is implicated in numerous diseases ranging from cancer to neurodegenerative diseases, making them a major target class for the pharmaceutical industry. However, the high degree of conservation that exists between ATP-binding sites among kinases makes it difficult for current inhibitors to be highly specific. In the context of neurodegeneration, several groups including ours, have linked different kinases such as CK1 and Alzheimer's disease for example. Strictly CK1-isoform specific regulators do not exist and known CK1 inhibitors are inhibiting the enzymatic activity, targeting the ATP-binding site. Here we review compounds known to target CK1, as well as other inhibitory types that could benefit CK1. We introduce the DNA-encoded library (DEL) technology that might represent an interesting approach to uncover allosteric modulators instead of ATP competitors. Such a strategy, taking into account known allosteric inhibitors and mechanisms, might help designing modulators that are more specific towards a specific kinase, and in the case of CK1, toward specific isoforms.

Automated summary

Protein kinases are essential in biology and their deregulation is linked to various diseases. However, the high conservation of ATP-binding sites among kinases makes it challenging to develop highly specific inhibitors. In the context of neurodegenerative diseases, CK1 and other kinases have been implicated. Currently, there are no specific regulators for CK1, and known inhibitors target the ATP-binding site. DNA-encoded library technology may be a promising approach to discover allosteric modulators instead of ATP competitors.