Discovery of small molecule Gq/11 protein inhibitors against uveal melanoma.

Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated Gq/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma (UM) cases, making directly targeting Gq/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as Gq/11 inhibitors, and identified GQ262 with improved Gq/11 inhibitory activity and drug-like properties. GQ262 efficiently blocked UM cell proliferation and migration . 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 Gq/11 directly. Significantly, GQ262 showed outstanding antitumor efficacy with good safety at the testing dose. Collectively, our findings along with the favorable pharmacokinetics of GQ262 revealed that directly targeting Gq/11 may be an efficient strategy against uveal melanoma.