L013 promotes NRF2 degradation in NRFA-subtype esophageal squamous cell carcinoma.

NRF2 oncogenic activation (NRFA)-subtype esophageal squamous cell carcinoma (ESCC) patients exhibit poor prognosis and limited response to conventional therapies due to excessive NRF2 protein accumulation. Here, we identify L013, an NRF2 degrader, through high-content screening of 725 cereblon (CRBN) ligand-based degraders. Our results indicate that L013 effectively reduces NRF2 abundance and decreases NFE2L2 mRNA expression in ESCC cells. Mechanistically, L013 promotes NRF2 ubiquitination through a ubiquitin-proteasome system (UPS)-associated process involving Cullin-dependent E3 ligase activity, while its A51-derived scaffold independently contributes to NRF2 suppression, at least in part, by impairing NFE2L2 transcriptional output. In preclinical models, L013 reduces NRF2 levels and suppresses tumor growth in patient-derived organoids (PDOs) of ESCC and lung squamous cell carcinoma (LUSC), as well as ESCC xenograft models. No overt systemic toxicity occurs under the tested dosing regimen. Our findings establish L013 as a promising therapeutic candidate for NRFA-subtype ESCC patients, offering a potential strategy to target NRF2-driven oncogenesis.