Vividion Publishes Discovery of First-in-Class KEAP1 Activator, Supporting Ongoing Clinical Program in Oncology

Vividion Therapeutics published a study in Cancer Discovery describing small molecules that activate KEAP1 through a covalent allosteric molecular glue mechanism to drive degradation of NRF2, a transcription factor implicated in tumor growth, immune suppression and resistance to therapy.

Preclinical data reported by the company show antitumor activity and increased sensitivity to multiple chemotherapies and radiotherapy across several NRF2-dependent cancer models, including non-small cell lung cancer, esophageal squamous cell carcinoma and head and neck squamous cell carcinoma.

NRF2 has been difficult to target directly because it lacks canonical small-molecule binding pockets. Using a covalent-first chemoproteomics platform, researchers identified electrophilic small molecules that covalently bind a specific cysteine residue on KEAP1 (C151). Binding at C151 induces an allosteric conformational change that stabilizes KEAP1’s interaction with the CUL3 E3 ligase complex, restoring KEAP1-mediated NRF2 degradation.

In tumor models, these KEAP1 activators produced robust suppression of NRF2 signaling and meaningful antitumor activity. Pharmacologic NRF2 degradation also potentiated the effects of multiple chemotherapies and radiotherapy, suggesting KEAP1 activation could help overcome treatment resistance in NRF2-driven cancers.

“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,” said Aleksandra Rizo, M.D., Ph.D., President and Chief Executive 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,” said Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion.

Vividion’s lead KEAP1 activator, VVD-037, is being evaluated in a Phase I clinical trial (NCT05954312) in patients with solid tumors characterized by NRF2 pathway activation.

Vividion Therapeutics, a clinical-stage biopharmaceutical company and a wholly owned, independently operated subsidiary of Bayer AG, uses chemoproteomics and a proprietary covalent chemistry library to identify and advance small-molecule therapeutics against traditionally undruggable targets in oncology and immunology.