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Modulation of the 14-3-3σ/C-RAF "Auto"inhibited Complex by Molecular Glues
Markella Konstantinidou1, Holly R Vickery1, Marloes A M Pennings2
1Department of Pharmaceutical Chemistry and Small Molecule Discovery Center (SMDC), University of California San Francisco, San Francisco, California 94143, United States.
Journal of the American Chemical Society
|January 30, 2026
Summary
New molecular glues stabilize a key protein complex in the MAPK pathway, offering a novel approach for targeting cancer and RASopathies. These glues modulate protein-protein interactions previously considered undruggable.
Area of Science:
- Biochemistry
- Chemical Biology
- Drug Discovery
Background:
- Protein-protein interactions (PPIs) are crucial in cellular signaling pathways like MAPK.
- The 14-3-3 protein and C-RAF interaction is a key regulatory point in the MAPK pathway.
- Targeting PPIs, especially those involving scaffolding proteins, presents challenges in drug discovery.
Purpose of the Study:
- To design and characterize molecular glues that stabilize the 14-3-3/C-RAFpS259 inhibitory complex.
- To explore the potential of molecular glues for modulating the MAPK pathway.
- To develop chemical probes for previously untargeted regulatory sites.
Main Methods:
- Fragment-merging approach to design molecular glues.
- Crystallography and biophysical studies to confirm mechanism of action.
- Cellular assays to evaluate on-target engagement and pathway modulation.
Main Results:
- Molecular glues stabilized the 14-3-3/C-RAFpS259 complex up to 300-fold.
- Compounds demonstrated high selectivity among RAF isoforms and 14-3-3 clients.
- In cellular assays, glues enhanced C-RAFpS259 phosphorylation and reduced RAF dimerization and ERK phosphorylation.
Conclusions:
- Molecular glues are effective tools for stabilizing native protein complexes at previously undruggable sites.
- This approach provides new chemical probes and drug discovery starting points for MAPK pathway modulation.
- Applications include oncology and the treatment of RASopathies.
