期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 32, 页码 17514-17521出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202101864
关键词
A549 cells; cell cycle arrest; Macrophage migration inhibitory factor (MIF); Mitogen-activated protein kinase (MAPK) pathway; proteolysis targeting chimera (PROTACs)
资金
- China Scholarship Council [201706010341, 201907720019]
- University of Groningen
The development of a MIF-targeted PROTAC, MD13, is able to induce MIF degradation at low concentrations and suppress the proliferation of inflammatory and cancer cells, demonstrating the potential therapeutic value of PROTACs in cancer treatment.
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.
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