A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth

  • Cancer Discov. 2026 May 1;16(5):953-975. doi: 10.1158/2159-8290.CD-25-1187.
Nilotpal Roy  1 ,  Tine Wyseure  1 ,  I-Chung Lo  2 ,  Justine Lu  1 ,  Christie L Eissler  1 ,  Steffen M Bernard  1 ,  Ilah Bok  3 ,  Aaron N Snead  1 ,  Albert Parker  1 ,  U-Ging Lo  1 ,  Jason C Green  1 ,  Jordon Inloes  1 ,  Sarah R Jacinto  1 ,  Brent Kuenzi  1 ,  Marie Pariollaud  1 ,  Kathleen Negri  1 ,  Khoi Le  1 ,  Benjamin D Horning  1 ,  Noah Ibrahim  1 ,  Stephanie Grabow  1 ,  Harit Panda  4 ,  Dhaval P Bhatt  3 ,  Emily M Wilkerson  3 ,  Soma Saeidi  3 ,  Paul Zolkind  4 ,  Zoe Rush  1 ,  Heather N Williams  1 ,  Eric Walton  1 ,  Martha K Pastuszka  1 ,  John J Sigler  1 ,  Eileen Tran  1 ,  Kenneth Hee  5 ,  Joseph McLaughlin  1 ,  Géza Ambrus-Aikelin  6 ,  Jonathan Pollock  1 ,  Robert T Abraham  7 ,  Todd M Kinsella  8 ,  Gabriel M Simon  1 ,  Michael B Major  3  4 ,  David S Weinstein  1 ,  Matthew P Patricelli  1
Affiliations
  • 1. Vividion Therapeutics, San Diego, California.
  • 2. Degron Therapeutics, San Diego, California.
  • 3. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
  • 4. Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
  • 5. Sciex, Carlsbad, California.
  • 6. Genesis Therapeutics, San Diego, California.
  • 7. Engine Biosciences, Redwood City, California.
  • 8. Expedition Medicines, Cambridge, Massachusetts.
PMID: 41417010 DOI: 10.1158/2159-8290.CD-25-1187
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.

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