Abstact

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:beta-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 beta-catenin and beta-TrCP. We now find that NRX-252114 can also enhance the association between beta-TrCP and NRF2 phosphodegron peptides. To leverage this novel interaction for the development of NRF2:beta-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:beta-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 beta-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.