TY - JOUR
T1 - Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos
AU - Chen, Deng
AU - Osipyan, Angelina
AU - Adriana, Jeaunice
AU - Kader, Mohammed
AU - Gureev, Maxim
AU - Knol, Catharina W. J.
AU - Sigmund, Marie Cathérine
AU - Xiao, Zhangping
AU - van der Wouden, Petra E.
AU - Cool, Robbert H.
AU - Poelarends, Gerrit J.
AU - Dekker, Frank J.
N1 - Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/7/13
Y1 - 2023/7/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85164376968&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c00397
DO - 10.1021/acs.jmedchem.3c00397
M3 - Article
C2 - 37352470
AN - SCOPUS:85164376968
SN - 0022-2623
VL - 66
SP - 8767
EP - 8781
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -