Targeting the Interaction of NRF2 and β-TrCP with Molecular Glues - PubMed
6 hours ago
- #cancer therapeutics
- #NRF2 pathway
- #molecular glues
- Inhibiting the oncogenic driver NRF2 in non-small cell lung cancer (NSCLC) is a promising clinical opportunity.
- Molecular glues that enhance the NRF2:β-TrCP interaction could promote NRF2 degradation, offering therapeutic potential.
- NRX-252114, a known molecular glue for β-catenin, also enhances interaction between β-TrCP and NRF2 phosphodegron peptides.
- A library of chemical analogues was synthesized and evaluated using homology modeling and X-ray crystallography.
- Structural elucidation revealed occlusion of the molecular glue binding pocket in the NRF2:β-TrCP complex.
- This explains limited affinity enhancement for analogues and lack of NRF2 degradation in cells.
- Findings broaden the scope of β-TrCP-targeted glues, show NRF2 is glueable at peptide level, and provide guidance for future NRF2 pathway targeting.