On December 22, 2025 Vividion Therapeutics, Inc. (Vividion), a clinical-stage biopharmaceutical company, and a wholly owned and independently operated subsidiary of Bayer AG, reported the publication of a manuscript describing the discovery and preclinical characterization of small molecules that activate KEAP1 via a novel covalent allosteric molecular glue mechanism to drive degradation of NRF2.
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The article, "A covalent allosteric molecular glue suppresses NRF2-dependent cancer growth" (Roy et al., Cancer Discov.), establishes NRF2 degradation via KEAP1 activation as a promising therapeutic approach for NRF2-activated cancers, including non-small cell lung cancer, esophageal squamous cell carcinoma, and head and neck squamous cell carcinoma.
"NRF2 has long stood as a symbol of undruggable cancer biology. Our team has opened a new chapter in targeting this critical cancer pathway through the discovery of KEAP1 activators," said Aleksandra Rizo, M.D., Ph.D., President and Chief Executive Officer of Vividion. "This research reflects the power of our platform to reveal unexpected allosteric mechanisms that could directly contribute to improved therapeutic efficacy, and ultimately better patient outcomes, for people with hard-to-treat cancers."
NRF2 is a transcription factor that promotes tumor growth, immune suppression, and resistance to cancer therapies. However, despite its clear role in disease progression, NRF2 has resisted direct pharmacologic inhibition due to its lack of canonical small-molecule binding pockets. Using Vividion’s covalent-first chemoproteomics platform, researchers discovered electrophilic small molecules that covalently bind to a specific cysteine residue on KEAP1 (C151) and induce an allosteric conformational change that enhances KEAP1’s interaction with the CUL3 E3 ligase complex. This stabilization of the KEAP1-CUL3 complex restores KEAP1’s ability to drive NRF2 degradation.
In preclinical models, these KEAP1 activators led to robust suppression of NRF2 signaling and showed meaningful antitumor activity across several tumor types with NRF2 pathway activation. Importantly, pharmacologic NRF2 degradation also enhanced the effects of multiple chemotherapies and radiotherapy, supporting the therapeutic potential of KEAP1 activation in overcoming treatment resistance in NRF2-driven cancers. Collectively, these findings provide a strong mechanistic and translational rationale for the clinical evaluation of KEAP1 activators.
"By showing that KEAP1 can be pharmacologically activated, Vividion has pioneered a new therapeutic approach to treating NRF2-driven cancers," said Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion. "Mechanistic insights from these studies informed the design of our clinical KEAP1 activator, VVD-037, and its rational combinations with other cancer therapies. We’re excited to continue to explore its potential across the many cancer types driven by NRF2 dysregulation."
VVD-037, Vividion’s lead KEAP1 activator, is currently being evaluated in a Phase I clinical trial (NCT05954312) in patients with solid tumors characterized by NRF2 pathway activation.
(Press release, Vividion Therapeutics, DEC 22, 2025, View Source [SID1234661583])