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<p><i>Candida albicans</i> 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 <i>C. albicans</i> 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 <i>C. albicans</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月4日

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  • 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,
  • Leah E. Cowen

摘要

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.