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

Deng Chen, Angelina Osipyan, Jeaunice Adriana, Mohammed Kader, Maxim Gureev, Catharina W.J. Knol, Marie Cathérine Sigmund, Zhangping Xiao, Petra E. van der Wouden, Robbert H. Cool, Gerrit J. Poelarends, Frank J. Dekker*

*Corresponding author for this work

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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.

Original languageEnglish
Pages (from-to)8767-8781
Number of pages15
JournalJournal of Medicinal Chemistry
Issue number13
Publication statusPublished - 13-Jul-2023

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