Discovery of small molecule Gαq/11 protein inhibitors against uveal melanoma

Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated Gaq/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma(UM) cases, making directly targeting Gaq/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as Gaq/11 inhibitors, and identified GQ262 with improved Gaq/11 inhibitory activity and drug-like properties. GQ262 efficiently blocked UM cell proliferation and migration in vitro. Analysis of the apoptosis-related proteins, extracellular signal-regulated kinase(ERK), and yes-associated protein(YAP) demonstrated that GQ262 distinctly induced UM cells apoptosis and disrupted the downstream effectors by targeting Gaq/11directly. Significantly, GQ262 showed outstanding antitumor efficacy in vivo with good safety at the testing dose. Collectively, our findings along with the favorable pharmacokinetics of GQ262 revealed that directly targeting Gaq/11 may be an efficient strategy against uveal melanoma.