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Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells
Author(s) -
Xiao Zhangping,
Song Shanshan,
Chen Deng,
Merkerk Ronald,
Wouden Petra E.,
Cool Robbert H.,
Quax Wim J.,
Poelarends Gerrit J.,
Melgert Barbro N.,
Dekker Frank J.
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202101864
Subject(s) - macrophage migration inhibitory factor , proteolysis , chemistry , mapk/erk pathway , chimera (genetics) , microbiology and biotechnology , a549 cell , cancer research , inflammation , cell growth , cancer cell , cancer , cell , signal transduction , biology , cytokine , biochemistry , immunology , enzyme , genetics , gene
Abstract Macrophage migration inhibitory factor (MIF) is involved in protein‐protein interactions that play key roles in inflammation and cancer. Current strategies to develop small molecule modulators of MIF functions are mainly restricted to the MIF tautomerase active site. Here, we use this site to develop proteolysis targeting chimera (PROTAC) in order to eliminate MIF from its protein‐protein interaction network. We report the first potent MIF‐directed PROTAC, denoted MD13 , which induced almost complete MIF degradation at low micromolar concentrations with a DC 50 around 100 nM in A549 cells. MD13 suppresses the proliferation of A549 cells, which can be explained by deactivation of the MAPK pathway and subsequent induction of cell cycle arrest at the G2/M phase. MD13 also exhibits antiproliferative effect in a 3D tumor spheroid model. In conclusion, we describe the first MIF‐directed PROTAC ( MD13 ) as a research tool, which also demonstrates the potential of PROTACs in cancer therapy.