Targeting a Novel Binding Pocket on Gαq in GNAQ-Mutant Uveal Melanoma

Uveal melanoma is frequently driven by activating mutations in GNAQ or GNA11, which encode the Gαq and Gα11 protein subunits. These mutations impair GTPase activity, leading to prolonged signaling that supports tumor development and survival. Targeting aberrant Gαq signaling is therefore a promising therapeutic strategy for GNAQ-mutant uveal melanoma.

In this project, we identified a novel, potential binding pocket on Gαq. Our internally developed AI-based screening methods do not depend on previously known ligands or characterized binding sites, which makes them well suited to searching for small molecules against pockets that have not been explored before.

Using this approach, we identified compounds predicted to bind within this pocket. In early cell-based assays, several of these compounds, including both approved drugs and novel compounds, showed biological activity in uveal melanoma cell lines. These results are preliminary and require further testing.

Further experimental studies are underway with Roger Olofsson Bagge research group. They will test additional compounds, assess selectivity, and determine whether the observed activity is mediated through direct binding to Gαq.