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

A study published in Cancer Discovery describes the discovery and preclinical characterization of small molecules that activate KEAP1 by a novel covalent allosteric molecular glue mechanism to promote degradation of the transcription factor NRF2, a driver of treatment resistance in multiple cancers.

Using a covalent-first chemoproteomics platform, researchers identified electrophilic compounds that covalently bind cysteine 151 on KEAP1 and induce an allosteric change that stabilizes the KEAP1–CUL3 E3 ligase complex. This restored KEAP1 activity drives ubiquitin-mediated degradation of NRF2, overcoming a long-standing barrier to targeting NRF2-driven tumors that lack canonical small-molecule binding pockets.

In preclinical models, KEAP1 activation led to robust suppression of NRF2 signaling and produced antitumor activity across multiple NRF2-dependent cancer types, including non-small cell lung cancer, esophageal squamous cell carcinoma, and head and neck squamous cell carcinoma. Pharmacologic NRF2 degradation also enhanced responses to several chemotherapies and to radiotherapy, suggesting potential to overcome therapy resistance in NRF2-activated tumors.

Vividion Therapeutics said mechanistic insights from these studies informed the design of its clinical KEAP1 activator, VVD-037, which is currently being evaluated in a Phase I trial (NCT05954312) in patients with solid tumors characterized by NRF2 pathway activation.

“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. Aleksandra Rizo, M.D., Ph.D., President and CEO, noted the findings reflect the company’s platform capability to reveal unexpected allosteric mechanisms with potential therapeutic impact.

Vividion Therapeutics, a wholly owned and independently operated subsidiary of Bayer AG, is a clinical-stage biopharmaceutical company that applies chemoproteomic and covalent chemistry platforms to identify and drug challenging targets in oncology and immunology. The company states its programs aim to advance selective small-molecule therapeutics against traditionally undruggable proteins.