WRN helicase is an enzyme that maintains genomic stability and integrity. Cancer cells that are defective in a specific type of DNA repair exhibit microsatellite instability (MSI) in their genomic DNA and depend on this enzyme for growth and viability. WRN inhibition could be used to specifically target MSI-positive cancers.

VVD-214 is a WRN inhibitor designed to prevent MSI repair without harming healthy cells to treat MSI-positive cancers, including subsets of colorectal, endometrial, and gastric cancers.

KEAP1 is an E3 ligase that degrades NRF2, a master regulatory transcription factor that coordinates antioxidant, detoxification, and cytoprotective gene programs. Gain-of-function mutations in NRF2 or loss-of-function mutations in KEAP1 lead to pathway activation, which can promote malignant tumor growth and resistance to many standard-of-care therapies. These mutations are most frequently detected in solid cancers, such as non-small cell lung cancer, esophageal squamous cell carcinoma, and head and neck squamous cell carcinoma.

VVD-037 is a highly selective, first-in-class small molecule activator of KEAP1 that allosterically enhances the ability of this E3 ligase to degrade its natural cellular target, NRF2. In preclinical models of NRF2-hyperactivated tumors, VVD-037-induced NRF2 depletion robustly inhibits tumor growth, as either a single agent or in combination with common chemotherapeutic agents and radiotherapy. Therapeutic targeting of NRF2 has the potential to dramatically shift the treatment paradigm of NRF2-activated cancers.

RAS proteins are membrane-bound GTPases that can cause multiple types of cancers by activating two signaling pathways, MAPK and PI3Kα. In preclinical models, it has been shown that simultaneous inhibition of these two signaling arms can effectively inhibit disease progression, but it has been difficult to implement this strategy clinically due to tolerability issues associated with the existing small molecules, which can disrupt homeostatic signaling through inhibition of the protein’s active site.

Vividion has discovered small molecules that inhibit RAS-dependent PIK3CA oncogenic signaling by specifically blocking the interaction between RAS and PIK3CA, without disrupting homeostatic signaling. Our molecules show dramatic benefit in pre-clinical models of RAS-driven cancers when combined with therapies targeting the MAPK pathway. In addition, we have found that this same mechanism is effective at countering adaptive resistance to RAS inhibitors. We therefore anticipate that our RAS-PIK3CA inhibitors will have broad clinical utility, particularly as part of rational combination therapies in RAS-driven cancers.

Leveraging our covalent-first chemoproteomics platform, we identify and characterize functional sites on proteins linked to diseases with high unmet need, and design highly selective small-molecule drugs to precisely modulate these targets. This approach enables the discovery of first-in-class programs and supports our broader goal of delivering differentiated medicines for patients.