Development of a Chemical Probe to Enable Characterization of the Casein Kinase 1γ Subfamily
The casein kinase 1γ (CK1γ) 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 CK1γ, the selective inhibition of CK1γ 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 CK1γ subfamily in cells. Enabled by these assays, we conducted a comprehensive structure-activity relationship (SAR) campaign to develop the first chemical probe, SGC-CK1γ-1, for the CK1γ subfamily. SGC-CK1γ-1, which was developed alongside a structurally related negative control compound, potently and selectively inhibited the CK1γ kinases in living cells, plus inhibited both WNT signaling and human cytomegalovirus replication.
Authors
- Catherine M. K. Ho
- Jacob L. Capener (ORCID: https://orcid.org/0000-0001-5051-2010)
- Frances M. Bashore (ORCID: https://orcid.org/0000-0003-4241-9873)
- Thomas Krämer (ORCID: https://orcid.org/0000-0003-0507-7843)
- E Flory (ORCID: https://orcid.org/0009-0002-5926-269X)
- F. Li (ORCID: https://orcid.org/0000-0003-1442-3277)
- Alison D. Axtman
Institutions
- University of North Carolina at Chapel Hill (US)
- University of Toronto (CA)
- Structural Genomics Consortium (CA)
- Universidad de Londres (MX)
- Institute of Infection and Immunity (CA)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-01-26
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02609
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Pharmaceutical Research and Manufacturers of America Foundation
- Pfizer
- Bayer
- North Carolina Biotechnology Center
- McGill University
- Genome Canada
- Merck KGaA
- Ontario Genomics
- European Federation of Pharmaceutical Industries and Associations
- Ontario Genomics Institute
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- National Institutes of Health
- Genentech
- St. George's, University of London
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill