Design, Synthesis, and Evaluation of Small Molecule Gαq/11 Protein Inhibitors for the Treatment of Uveal Melanoma

Uveal
melanoma is the ocular malignancy and mainly driven by oncogenic
mutations of Gαq/11 proteins. Previous targeted therapy for
melanoma treatment was limited to specific downstream signaling pathway,
and inhibiting the “molecular switches” G proteins for
melanoma treatment therapy was rarely described. We herein report
the discovery of imidazopiperazine derivatives as Gαq/11 protein
inhibitors. The most promising compound GQ127 showed
good efficacy and safety in inositol monophosphate (IP1) assay by directly inhibiting Gαq/11 proteins. GQ127 induced uveal melanoma cells apoptosis and displayed potent antitumor
activities in uveal melanoma cells viability, migration, and invasion.
The effects of GQ127 on Gαq/11 signaling pathway
were confirmed by analyzing the downstream effectors yes-associated
protein (YAP) and extracellular signal-regulated kinase (ERK). More
importantly, GQ127 significantly suppressed UM xenograft
growth in mouse model without severe toxicity at the testing dose.
These findings provide a lead compound that directly targets the Gαq/11
proteins for uveal melanoma treatment.