9EDV

Crystal structure of Yck2 from Candida albicans in complex with inhibitor 1e: 2-(4-fluorophenyl)-3-(pyridin-4-yl)imidazo[1,2-a]pyridine-7-carbonitrile

This is a non-PDB format compatible entry.

Summary for 9EDV

• Entry DOI: 10.2210/pdb9edv/pdb
• Descriptor: non-specific serine/threonine protein kinase, 2-(4-fluorophenyl)-3-(pyridin-4-yl)imidazo[1,2-a]pyridine-7-carbonitrile, CHLORIDE ION (3 entities in total)
• Functional Keywords: yck2, kinase, kinase inhibitor, structural genomics, niaid, national institute of allergy and infectious diseases, center for structural biology of infectious diseases, csbid, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Candida albicans
• Total number of polymer chains: 1
• Total formula weight: 35747.02

Authors

Stogios, P.J.,Whitesell, L.,Cowen, L.E.,Savchenko, A.,Joachimiak, A.,Satchell, K.J.F.,Center for Structural Biology of Infectious Diseases (CSBID) (deposition date: 2024-11-18, release date: 2025-01-08, Last modification date: 2025-09-24)

Primary citation

Puumala, E.,Nandakumar, M.,Yiu, B.,Stogios, P.J.,Strickland, B.G.,Zarnowski, R.,Wang, X.,Williams, N.S.,Savchenko, A.,Andes, D.R.,Robbins, N.,Whitesell, L.,Willson, T.M.,Cowen, L.E.
Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans.
Nat Commun, 16:2156-2156, 2025

PubMed 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.

PubMed: 40038303
DOI: 10.1038/s41467-025-57346-z

Experimental method

X-RAY DIFFRACTION (2.42 Å)