Uveal melanoma is a rare but highly lethal eye cancer in which more than half of patients develop metastatic disease with poor long-term survival. Therapeutic options are limited, with immunotherapies benefiting only select subgroups and inhibitors of downstream signaling pathways frequently leading to resistance. Despite these challenges, the genetic basis of uveal melanoma is unusually clear. Over 90 percent of tumors harbor activating mutations in Gαq or Gα11, heterotrimeric G protein alpha subunits that initiate oncogenic signaling. A major unmet need in the field is the development of therapies that directly target these dominant genetic drivers rather than their downstream effectors.
This Drug Discovery Award builds on prior discoveries supported by a Mark Foundation ASPIRE Award, which demonstrated that oncogenic Gαq adopts conformations distinct from the wild-type protein and enabled the identification of selective small-molecule binders. The current project advances these findings through two complementary approaches. First, the team will optimize early hits into potent and selective inhibitors that disrupt a key pathogenic interaction using structure-guided medicinal chemistry. In parallel, they will conduct large-scale high-throughput and DNA-encoded library screens to discover new chemical matter that selectively targets oncogenic Gαq and Gα11. They will refine validated compounds using structural biology, iterative chemistry, and functional testing in uveal melanoma cell models to ensure efficacy and spare wild-type signaling.
By directly targeting the root oncogenic drivers of uveal melanoma, this project addresses a long-standing challenge in this rare but devastating tumor. If successful, the project is expected to yield advanced lead compounds within 24 to 36 months and could lay the foundation for the first therapies specifically designed to treat patients with Gαq or Gα11-driven uveal melanoma.