2. Academic Validation
  3. Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti-Proliferative Activity in Lung Cancer Cells

Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti-Proliferative Activity in Lung Cancer Cells

  • Angew Chem Int Ed Engl. 2021 Aug 2;60(32):17514-17521. doi: 10.1002/anie.202101864.
Zhangping Xiao 1,  Shanshan Song 1 2,  Deng Chen 1,  Ronald van Merkerk,  Petra E van der Wouden 1,  Robbert H Cool 1,  Wim J Quax 1,  Gerrit J Poelarends 1,  Barbro N Melgert 2 3,  Frank J Dekker 1
Affiliations

Affiliations

  • 1 Department Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands.
  • 2 Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713, AV, Groningen, The Netherlands.
  • 3 University Medical Center Groningen, Groningen Research Institute of Asthma and COPD, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
PMID: 34018657 DOI: 10.1002/anie.202101864
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 DC50 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.

Keywords

A549 cells; Macrophage migration inhibitory factor (MIF); Mitogen-activated protein kinase (MAPK) pathway; cell cycle arrest; proteolysis targeting chimera (PROTACs).

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