Development of a chemical probe to enable characterization of the casein kinase 1γ subfamily.
| Title: | Development of a chemical probe to enable characterization of the casein kinase 1γ subfamily. |
|---|---|
| Authors: | Capener JL; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Kramer TW; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Bashore FM; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Flory E; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Li F; Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.; Strang BL; Institute for Infection & Immunity, City St George's, University of London, London, SW17 0RE, UK.; Axtman AD; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2025 Sep 16. Date of Electronic Publication: 2025 Sep 16. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| Abstract: | 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. |
| Competing Interests: | The authors declare no competing financial interest. |
| Comments: | Update in: J Med Chem. 2026 Feb 12;69(3):2666-2684. doi: 10.1021/acs.jmedchem.5c02609.. (PMID: 41587072) |
| Grant Information: | P30 CA016086 United States CA NCI NIH HHS; S10 OD032476 United States OD NIH HHS; U24 DK116204 United States DK NIDDK NIH HHS; U54 AG065187 United States AG NIA NIH HHS |
| Entry Date(s): | Date Created: 20250926 Date Completed: 20260203 Latest Revision: 20260213 |
| Update Code: | 20260213 |
| PubMed Central ID: | PMC12458359 |
| DOI: | 10.1101/2025.09.10.675406 |
| PMID: | 41000769 |
| Database: | MEDLINE |
Journal Article; Preprint