A covalent allosteric molecular glue suppresses NRF2-dependent cancer growth
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 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 KEAP1_Cys151 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).
Authors
- Jason C. Green (ORCID: https://orcid.org/0009-0002-2975-1652)
- Michael B. Major (ORCID: https://orcid.org/0000-0002-6753-8513)
- Robert T. Abraham (ORCID: https://orcid.org/0000-0002-1258-0028)
- Dhaval P. Bhatt (ORCID: https://orcid.org/0000-0002-2037-9332)
- Matthew P. Patricelli (ORCID: https://orcid.org/0000-0002-7829-7065)
- Eric M. Walton (ORCID: https://orcid.org/0009-0009-8297-6261)
- Ilah Bok (ORCID: https://orcid.org/0000-0001-8958-5161)
- Géza Ambrus-Aikelin (ORCID: https://orcid.org/0000-0003-4504-7569)
- Khoi Le (ORCID: https://orcid.org/0009-0002-0824-0730)
- Kenneth Hee (ORCID: https://orcid.org/0009-0008-9337-2845)
- Christie L. Eissler (ORCID: https://orcid.org/0009-0008-9632-0645)
- Emily Wilkerson (ORCID: https://orcid.org/0000-0002-9360-7340)
- Noah Ibrahim (ORCID: https://orcid.org/0009-0003-4681-4333)
- Todd M. Kinsella (ORCID: https://orcid.org/0009-0004-3156-3452)
- Aaron N. Snead (ORCID: https://orcid.org/0009-0005-5251-0226)
- Benjamin D. Horning (ORCID: https://orcid.org/0000-0003-1772-4489)
- Jordon Inloes (ORCID: https://orcid.org/0009-0000-1615-0423)
- Nilotpal Roy (ORCID: https://orcid.org/0009-0009-9899-0092)
- Brent M. Kuenzi (ORCID: https://orcid.org/0000-0002-6771-0432)
- Steffen M. Bernard (ORCID: https://orcid.org/0000-0001-8061-6136)
- Aulma R. Parker (ORCID: https://orcid.org/0009-0008-1837-5878)
- I‐Chung Lo (ORCID: https://orcid.org/0000-0002-2632-3436)
- Harit Panda (ORCID: https://orcid.org/0000-0002-8209-5212)
- David S. Weinstein (ORCID: https://orcid.org/0000-0002-9799-2661)
- Stephanie Grabow (ORCID: https://orcid.org/0000-0003-0467-7871)
- Tine Wyseure (ORCID: https://orcid.org/0000-0003-2337-3443)
- G Simon (ORCID: https://orcid.org/0000-0002-5960-5536)
- Kathleen R. Negri (ORCID: https://orcid.org/0000-0001-6997-213X)
- Paul Zolkind (ORCID: https://orcid.org/0000-0002-9475-1686)
- Marie Pariollaud (ORCID: https://orcid.org/0000-0003-2325-6394)
- Justine Lu (ORCID: https://orcid.org/0009-0005-6669-920X)
- Joseph S. McLaughlin (ORCID: https://orcid.org/0009-0003-8277-7330)
- Jonathan Pollock (ORCID: https://orcid.org/0000-0002-5656-2753)
- Zoe Rush (ORCID: https://orcid.org/0009-0008-0041-5464)
- Eileen Tran (ORCID: https://orcid.org/0009-0002-3460-098X)
- U‐Ging Lo (ORCID: https://orcid.org/0009-0007-7055-2416)
- Heather N. Williams (ORCID: https://orcid.org/0009-0001-6437-770X)
- S. Saeidi (ORCID: https://orcid.org/0009-0001-5314-736X)
- Martha K. Pastuszka (ORCID: https://orcid.org/0009-0009-4139-3350)
- John J. Sigler (ORCID: https://orcid.org/0009-0006-4994-9497)
- Sarah Jacinto (ORCID: https://orcid.org/0009-0004-4017-2058)
Institutions
- IDEXX Laboratories (France) (FR)
- Washington University in St. Louis (US)
- Electronic BioSciences (United States) (US)
- Precision Therapeutics (United States) (US)
- BD Biosciences (United States) (US)
- Vividion Therapeutics (United States) (US)
- Washington University Medical Center (US)
- Genesis Medical Center (US)
- IMGENEX India (India) (IN)
- Genesis Research Institute (JP)
- Oldham Council (GB)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2025-12-19
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-1187
- Citations
- 3
- Primary Topic
- Genomics, phytochemicals, and oxidative stress
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- U.S. Department of Energy
- Bayer
- National Institutes of Health
- Office of Science
- National Cancer Institute
- National Institute of General Medical Sciences