AI Article Synopsis
- Macrophage migration inhibitory factor (MIF) plays a key role in inflammation and cancer through protein-protein interactions, and current methods to target MIF mainly focus on its active site.
- Researchers developed a proteolysis targeting chimera (PROTAC) called MD13, which effectively degrades MIF and reduces its influence in cellular interactions at low concentrations.
- MD13 not only inhibits the growth of A549 cancer cells by disrupting the MAPK pathway and causing cell cycle arrest but also shows promise in a 3D tumor model, indicating its potential for use in cancer therapy.
Article 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 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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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362126 | PMC |
| http://dx.doi.org/10.1002/anie.202101864 | DOI Listing |
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