Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans
Candida albicans is the most common cause of life-threatening fungal infection in the developed world but remains a therapeutic challenge. Protein kinases have been rewarding drug targets across diverse indications but remain untapped for antifungal development. Previously, screening kinase inhibitors against C. albicans revealed a 2,3-aryl-pyrazolopyridine, GW461484A (GW), which targets casein kinase 1 (CK1) family member Yck2. Here, we report optimization of GW via two complementary approaches, synthesis of bioisosteres possessing an imidazo[1,2-a]pyridine core, and R-group substitution of GW's pyrazolo[1,5-a]pyridine core. Characterization of compounds reveals two 6-cyano derivatives with improved pharmacological properties that retain whole-cell bioactivity and selectivity for fungal Yck2 compared to human CK1α. Efficacy studies in mice indicate both analogs possess single-agent activity against C. albicans resistant to first-line echinocandin antifungals and potentiate non-curative echinocandin treatment. Results validate Yck2 as an antifungal target and encourage further development of inhibitors acting by this previously unexploited mode of action.
Authors
- Emily Puumala (ORCID: https://orcid.org/0009-0008-3371-5877)
- David R. Andes (ORCID: https://orcid.org/0000-0002-7927-9950)
- Nicole Robbins (ORCID: https://orcid.org/0000-0003-2821-9269)
- Robert Żarnowski (ORCID: https://orcid.org/0000-0001-6343-1500)
- Luke J. Whitesell (ORCID: https://orcid.org/0000-0001-6445-5766)
- Leah E. Cowen (ORCID: https://orcid.org/0000-0001-5797-0110)
- Xiaoyu Wang (ORCID: https://orcid.org/0000-0001-6548-3793)
- Alexei V. Savchenko (ORCID: https://orcid.org/0000-0002-5256-9237)
- Meganathan Nandakumar (ORCID: https://orcid.org/0000-0002-9093-2244)
- P.J. Stogios (ORCID: https://orcid.org/0000-0001-8663-1425)
- Timothy M. Willson (ORCID: https://orcid.org/0000-0003-4181-8223)
- Noelle Sevilir Williams (ORCID: https://orcid.org/0000-0003-1894-5742)
- Benjamin G. Strickland (ORCID: https://orcid.org/0009-0007-4241-2045)
- Bonnie Yiu
Institutions
- University of North Carolina at Chapel Hill (US)
- University of Wisconsin–Madison (US)
- University of Calgary (CA)
- University of Toronto (CA)
- Joint Center for Structural Genomics (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1038/s41467-025-57346-z
- Citations
- 11
- Primary Topic
- Antifungal resistance and susceptibility
- Type
- article
- Field-Weighted Citation Impact
- 15.36
Funders
- Foundation for the National Institutes of Health