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.

doi:10.1101/2024.10.04.616592

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bioRxiv · 10.1101/2024.10.04.616592

Suppression of NRF2-dependent cancer growth by a covalent allosteric molecular glue

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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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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.. 2024-10-05. Suppression of NRF2-dependent cancer growth by a covalent allosteric molecular glue. https://doi.org/10.1101/2024.10.04.616592

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