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 - Funding Information:
This project received funding from the European Union′s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 754425. D.C. received a Ph.D. scholarship from the China Scholarship Council, grant number 201907720019.
Funding Information:
The authors sincerely acknowledge Dr. Peter Fodran for the proofreading of the Supporting Information and for the helpful discussions. They thank Rick Oerlemans, Ran Zhang, and Prof. Dr. Matthew Groves for their assistance with the MST experiment. They also thank Dr. Hjalmar Permentier and Wim Huibers for the detailed HRMS analysis. The authors acknowledge Rita Setroikromo for the technical support, Pieter Tepper for the help with HPLC, and Ronald van Merkerk for the assistance with protein purification. This project received funding from the European Union′s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 754425. D.C. received a Ph.D. scholarship from the China Scholarship Council, grant number 201907720019.
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 -