Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos

摘要

Macrophage migrationinhibitory factor (MIF) is a multifunctionalcytokine and essential signaling protein associated with inflammationand cancers. One of the newly described roles of MIF is binding toapoptosis-inducing factor (AIF) that "brings" cellsto death in pathological conditions. The interaction between MIF andAIF and their nuclear translocation stands as a central event in parthanatos.However, classical competitive MIF tautomerase inhibitors do not interferewith MIF functions in parthanatos. In this study, we employed a pharmacophore-switchto provide allosteric MIF tautomerase inhibitors that interfere withthe MIF/AIF co-localization. Synthesis and screening of a focusedcompound collection around the 1,2,3-triazole core enabled identificationof the allosteric tautomerase MIF inhibitor 6y with lowmicromolar potency (IC50 = 1.7 PLUSMN; 0.1 mu;M). Thisinhibitor prevented MIF/AIF nuclear translocation and protects cellsfrom parthanatos. These findings indicate that alternative modes totarget MIF hold promise to investigate MIF function in parthanatos-mediateddiseases.