2. Academic Validation
  3. Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans

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

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. leah.cowen@utoronto.ca.
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.

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