{Reference Type}: Journal Article
{Title}: Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos.
{Author}: Chen D;Osipyan A;Adriana J;Kader M;Gureev M;Knol CWJ;Sigmund MC;Xiao Z;van der Wouden PE;Cool RH;Poelarends GJ;Dekker FJ;
{Journal}: J Med Chem
{Volume}: 66
{Issue}: 13
{Year}: 2023 07 13
{Factor}: 8.039
{DOI}: 10.1021/acs.jmedchem.3c00397
{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.