On January 6, 2026 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 detailing the discovery and optimization of VVD-214, the company’s covalent inhibitor of Werner helicase (WRN), on the cover of the Journal of Medicinal Chemistry. The article, "Identification of VVD-214/RO7589831, a Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers" (Kikuchi et al., J. Med. Chem.,December 2025), validates Vividion’s covalent-first chemoproteomics approach to reach targets that have eluded traditional drug discovery.
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"The discovery of VVD-214 marks a significant milestone in the development of a new class of potential therapies for MSI-high solid tumors," said Aleksandra Rizo, M.D., Ph.D., President and Chief Executive Officer of Vividion. "Patients with malignancies with high microsatellite instability (MSI) — including colorectal, endometrial, ovarian, and gastric cancers — have limited treatment options, and many ultimately relapse or become resistant to available therapies. This program’s continued progress, as the first covalent inhibitor in clinical development, underscores our platform’s ability to generate differentiated investigational medicines that address some of the toughest challenges in cancer biology."
VVD-214 is designed to exploit the dependency of MSI-high cancer cells on WRN-mediated DNA repair, leading to selective tumor cell death while sparing healthy tissue. In the manuscript, researchers report utilizing Vividion’s chemoproteomics platform to identify molecular fragments that covalently bound an allosteric pocket of WRN to lock it into an inactive conformation. These molecules were then optimized through iterative structure-activity relationship testing, with particular focus on the cysteine-reactive electrophile (vinyl sulfone) and the molecule’s core aromatic rings. The resulting structure of VVD-214 was chosen for its balance of potency, selectivity, and drug-like ADME properties. In preclinical studies, VVD-214 was well tolerated and led to robust tumor regression in multiple patient-derived xenograft mouse models of MSI-high colorectal cancer.
The compound is now in a Phase I clinical trial (NCT06004245) as monotherapy and in combination with pembrolizumab for patients with MSI-high or mismatch repair deficient (dMMR) cancers.
"WRN is a high-value oncology target known to induce synthetic lethality in cancers with high MSI, but as a helicase it has been extremely difficult to drug," said Matt Patricelli, Ph.D., Chief Scientific Officer of Vividion. "This paper highlights the strength of Vividion’s chemoproteomics platform at identifying selective small molecules against even the most challenging protein classes, while our medicinal chemistry expertise in covalent drug design enables us to optimize those discoveries into potent and selective therapeutic candidates."
(Press release, Vividion Therapeutics, JAN 6, 2026, View Source [SID1234661765])