Development of a chemical probe to enable characterization of the casein kinase 1γ subfamily

The casein kinase 1{gamma} (CK1{gamma}) subfamily, while severely understudied, is implicated in diverse disease-relevant pathways, including WNT signaling and human cytomegalovirus (HCMV) replication. While genetic tools exist to study CK1{gamma}, the selective inhibition of CK1{gamma} through pharmacological means remains underexplored. Chemical probes, or potent and selective inhibitors, remain one of the most powerful pharmacological tools for uncovering protein biology. Herein, we developed several novel assays for assessing target engagement with the CK1{gamma} subfamily in cells. Enabled by these assays, we conducted a comprehensive structure-activity relationship (SAR) campaign to develop the first chemical probe, SGC-CK1{gamma}-1, for the CK1{gamma} subfamily. SGC-CK1{gamma}-1, which was developed alongside a structurally related negative control compound, potently and selectively inhibited the CK1{gamma} kinases in living cells, plus inhibited both WNT signaling and human cytomegalovirus replication.