Suppression of NRF2-dependent cancer growth by a covalent allosteric molecular glue
Roy, N.; Wyseure, T.; Lo, I.-C.; Metzger, J.; Eissler, C. L.; Bernard, S. M.; Bok, I.; Snead, A. N.; Parker, A.; Green, J. C.; Inloes, J.; Jacinto, S. R.; Kuenzi, B.; Horning, B. D.; Ibrahim, N.; Grabow, S.; Panda, H.; Bhatt, D. P.; Saeidi, S.; Zolkind, P.; Rush, Z.; Negri, K.; Williams, H. N.; Walton, E.; Pastuszka, M. K.; Sigler, J. J.; Tran, E.; Hee, K.; McLaughlin, J.; Ambrus-Aikelin, G.; Pollock, J.; Abraham, R. T.; Kinsella, T. M.; Simon, G. M.; Major, M. B.; Weinstein, D. S.; Patricelli, M. P.
Show abstract
The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-dependency and resistance to chemo/radiotherapy. Here 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 KEAP1-CUL3 ubiquitin-ligase complex. VVD-065 specifically and covalently engages C151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported C151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_C151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312).
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