Targeting the Interaction of NRF2 and β-TrCP with Molecular Glues.
2/5 보강
OpenAlex 토픽 ·
Genomics, phytochemicals, and oxidative stress
Protein Degradation and Inhibitors
14-3-3 protein interactions
Inhibiting the oncogenic driver NRF2 in non-small cell lung cancer (NSCLC) represents a promising yet challenging clinical opportunity.
APA
Daniel H. O Donovan, Jon Winter-Holt, et al. (2026). Targeting the Interaction of NRF2 and β-TrCP with Molecular Glues.. ACS chemical biology, 21(4), 635-642. https://doi.org/10.1021/acschembio.5c01006
MLA
Daniel H. O Donovan, et al.. "Targeting the Interaction of NRF2 and β-TrCP with Molecular Glues.." ACS chemical biology, vol. 21, no. 4, 2026, pp. 635-642.
PMID
41910202 ↗
Abstract 한글 요약
Inhibiting the oncogenic driver NRF2 in non-small cell lung cancer (NSCLC) represents a promising yet challenging clinical opportunity. Small molecules that enhance the NRF2:β-TrCP interaction ("molecular glues") could hold therapeutic potential by promoting the ubiquitination and proteasomal degradation of NRF2. NRX-252114 is a molecular glue previously reported to promote the interaction between β-catenin and β-TrCP. We now find that NRX-252114 can also enhance the association between β-TrCP and NRF2 phosphodegron peptides. To leverage this novel interaction for the development of NRF2:β-TrCP molecular glues, we synthesized and evaluated a library of chemical analogues, guided by homology modeling and subsequently by X-ray crystallography. Surprisingly, structural elucidation of the NRF2:β-TrCP complex revealed occlusion of the presumed molecular glue binding pocket. This mechanistic insight explains the limited affinity enhancement for analogues of NRX-252114, and provides a structural rationale for the lack of NRF2 degradation in cells. Our findings broaden the scope of β-TrCP-targeted molecular glues, demonstrate that NRF2 is "glueable" at the peptide level, and provide mechanistic guidance for future efforts to target the pharmacologically elusive NRF2 pathway in cancer.
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