A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth
Nilotpal Roy, Tine Wyseure, I‐Chung Lo, Justine Lu, Christie L. Eissler, Steffen M. Bernard, Ilah Bok, Aaron N. Snead, Aulma R. Parker, U‐Ging Lo, Jason C. Green, Jordon M. Inloes, Sarah Jacinto, Brent M. Kuenzi, Marie Pariollaud, Kathleen R. Negri, Khoi Le, Benjamin D. Horning, Noah Ibrahim, Stephanie Grabow, Harit Panda, Dhaval P. Bhatt, Emily Wilkerson, S. Saeidi, Paul Zolkind, Zoe Rush, Heather N. Williams, Eric M. Walton, Martha K. Pastuszka, J. Sigler, Eileen Tran, Kenneth Hee, Joseph S. McLaughlin, Géza Ambrus-Aikelin, Jonathan Pollock, Robert T. Abraham, Todd M. Kinsella, G Simon, Michael B. Major, David S. Weinstein, Matthew P. Patricelli
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.