Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans

  • Nat Commun. 2025 Mar 4;16(1):2156. doi: 10.1038/s41467-025-57346-z.
Emily Puumala  1 ,  Meganathan Nandakumar  2 ,  Bonnie Yiu  1 ,  Peter J Stogios  3 ,  Benjamin G Strickland  2 ,  Robert Zarnowski  4 ,  Xiaoyu Wang  5 ,  Noelle S Williams  5 ,  Alexei Savchenko  3  6  7 ,  David R Andes  4 ,  Nicole Robbins  1 ,  Luke Whitesell  1 ,  Timothy M Willson  2 ,  Leah E Cowen  8
Affiliations
  • 1. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 2. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 3. Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada.
  • 4. Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
  • 5. Department of Biochemistry, University of Texas Southwestern Medical School, Dallas, TX, USA.
  • 6. Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • 7. Center for Structural Biology of Infectious Diseases (CSBID), Chicago, Illinois, USA.
  • 8. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [email protected].
PMID: 40038303 DOI: 10.1038/s41467-025-57346-z
Abstract

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.

Products