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

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.