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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)\u2013cullin3 (CUL3) ubiquitin-ligase complex. VVD-065 specifically and covalently engages Cys151 on KEAP1, which in turn promotes KEAP1\u2013CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported Cys151-directed compounds decrease KEAP1\u2013CUL3 interactions and stabilize NRF2, thus establishing KEAP1C151 as a tunable regulator of the KEAP1\u2013CUL3 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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>See related commentary by Hintzen and Burslem, p. 829<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-1187","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T15:43:12Z","timestamp":1766158992000},"page":"953-975","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9899-0092","authenticated-orcid":false,"given":"Nilotpal","family":"Roy","sequence":"first","affiliation":[{"name":"1Vividion Therapeutics, San Diego, 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