9EDX

Crystal structure of Yck2 from Candida albicans in complex with inhibitor 2a: 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6-carbonitrile

これはPDB形式変換不可エントリーです。

9EDX の概要

• エントリーDOI: 10.2210/pdb9edx/pdb
• 分子名称: non-specific serine/threonine protein kinase, 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-6-carbonitrile, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: yck2, kinase, kinase inhibitor, structural genomics, center for structural bioloy of infectious diseases, niaid, national institute of allergy and infectious diseases, transferase, transferase-inhibitor complex, center for structural biology of infectious diseases, csbid, transferase/inhibitor
• 由来する生物種: Candida albicans
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35782.48

構造登録者

Stogios, P.J.,Whitesell, L.,Cowen, L.E.,Savchenko, A.,Joachimiak, A.,Satchell, K.J.F.,Center for Structural Biology of Infectious Diseases (CSBID) (登録日: 2024-11-18, 公開日: 2025-01-08, 最終更新日: 2025-09-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.03 Å)