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

  • J Med Chem. 2023 Jul 13;66(13):8767-8781. doi: 10.1021/acs.jmedchem.3c00397.
Deng Chen  1 ,  Angelina Osipyan  1 ,  Jeaunice Adriana  1 ,  Mohammed Kader  1 ,  Maxim Gureev  2 ,  Catharina W J Knol  1 ,  Marie-Cathérine Sigmund  1 ,  Zhangping Xiao  1 ,  Petra E van der Wouden  1 ,  Robbert H Cool  1 ,  Gerrit J Poelarends  1 ,  Frank J Dekker  1
Affiliations
  • 1. Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
  • 2. Center of Chemo- and Bioinformatics, Institute of Biodesign and Complex Systems Modeling, I. M. Sechenov First Moscow State Medical University, 119991 Moscow, The Russian Federation.
PMID: 37352470 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.

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