A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth

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.