Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos.
J Med Chem
; 66(13): 8767-8781, 2023 07 13.
Article
en En
| MEDLINE
| ID: mdl-37352470
ABSTRACT
Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and essential signaling protein associated with inflammation and cancers. One of the newly described roles of MIF is binding to apoptosis-inducing factor (AIF) that "brings" cells to death in pathological conditions. The interaction between MIF and AIF and their nuclear translocation stands as a central event in parthanatos. However, classical competitive MIF tautomerase inhibitors do not interfere with MIF functions in parthanatos. In this study, we employed a pharmacophore-switch to provide allosteric MIF tautomerase inhibitors that interfere with the MIF/AIF co-localization. Synthesis and screening of a focused compound collection around the 1,2,3-triazole core enabled identification of the allosteric tautomerase MIF inhibitor 6y with low micromolar potency (IC50 = 1.7 ± 0.1 µM). This inhibitor prevented MIF/AIF nuclear translocation and protects cells from parthanatos. These findings indicate that alternative modes to target MIF hold promise to investigate MIF function in parthanatos-mediated diseases.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Factores Inhibidores de la Migración de Macrófagos
/
Parthanatos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Países Bajos