WNT974

WNT974, also known by its development code LGK974, is a small-molecule inhibitor of porcupine (PORCN), an enzyme essential for the secretion of Wnt ligands. By blocking PORCN, WNT974 reduces the production and release of Wnt proteins, thereby dampening Wnt signaling in tumor cells and the tumor microenvironment. The drug was developed as a targeted approach for cancers believed to depend on Wnt pathway activity.

In clinical development, WNT974 has been evaluated in early-phase trials for various advanced solid tumors and in combination regimens with chemotherapy or other therapies. Studies have explored its use as monotherapy and in combination with agents such as cytotoxic chemotherapy, and, in some protocols, with immune-modulating therapies. While some patients have shown signs of antitumor activity, there is no established regulatory approval for WNT974. Reported adverse events in early trials have generally been manageable, with common effects including fatigue and gastrointestinal symptoms; some trials have noted taste alterations, consistent with the broad role of Wnt signaling in normal tissues.

Safety considerations reflect the broad role of Wnt signaling in normal physiology. PORCN inhibition can impact tissues that rely on Wnt signaling for maintenance, such as the bone and intestinal epithelium, underscoring the need for careful monitoring and patient selection in ongoing development. Research continues to identify biomarkers of response and appropriate combination strategies to maximize potential benefit while managing risks. As an investigational agent, WNT974 has not received regulatory approval.