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

Emily Puumala, Meganathan Nandakumar, Bonnie Yiu, Peter J. Stogios, Benjamin G. Strickland, Robert Zarnowski, Xiaoyu Wang, Noelle S. Williams, Alexei Savchenko, David R. Andes, Nicole Robbins, Luke Whitesell, Timothy M. Willson and Leah E. Cowen ()
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Emily Puumala: University of Toronto
Meganathan Nandakumar: University of North Carolina at Chapel Hill
Bonnie Yiu: University of Toronto
Peter J. Stogios: University of Toronto
Benjamin G. Strickland: University of North Carolina at Chapel Hill
Robert Zarnowski: University of Wisconsin-Madison
Xiaoyu Wang: University of Texas Southwestern Medical School
Noelle S. Williams: University of Texas Southwestern Medical School
Alexei Savchenko: University of Toronto
David R. Andes: University of Wisconsin-Madison
Nicole Robbins: University of Toronto
Luke Whitesell: University of Toronto
Timothy M. Willson: University of North Carolina at Chapel Hill
Leah E. Cowen: University of Toronto

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57346-z

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