{"doi":"10.1158/2159-8290.cd-25-1187","title":"A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth","abstract":"The NRF2 transcription factor is constitutively active in cancer, in which it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2 dependency and resistance to chemotherapy/radiotherapy (RT). In this study, we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the Kelch-like ECH-associated protein 1 (KEAP1)-cullin3 (CUL3) ubiquitin-ligase complex. VVD-065 specifically and covalently engages Cys151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1C151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemotherapy/RT, supporting an open phase I clinical trial (NCT05954312). SIGNIFICANCE: NRF2 hyperactivation is frequently observed in various solid tumors, including lung, esophageal, and head and neck cancers, highlighting NRF2 as a potential therapeutic target. We report a first-in-class KEAP1-dependent allosteric molecular glue degrader of NRF2, which demonstrated robust monotherapy responses in NRF2-activated cancers and effectively sensitized chemo-refractory tumors to chemotherapy. See related commentary by Hintzen and Burslem, p. 829.","journal":"Cancer Discovery","year":2025,"id":513629,"datarank":0.5044949533258185,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.14481066240606288,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.14481066240606288,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":10,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9467,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT05954312"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1295799,"name":"Tine Wyseure","orcid":"0000-0003-2337-3443","position":1,"is_corresponding":false},{"id":530183,"name":"I‐Chung Lo","orcid":"0000-0002-2632-3436","position":2,"is_corresponding":false},{"id":1374823,"name":"Justine Lu","orcid":"0009-0005-6669-920X","position":3,"is_corresponding":false},{"id":1374824,"name":"Christie L. 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