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 Gαq/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma(UM)cases,making directly targeting Gαq/11 to be a promising strategy for combating UM.Herein,we report the optimization of imidazopiperazine derivatives as Gαq/11 inhibitors,and iden-tified GQ262 with improved Gαq/11 inhibitory activity and drug-like properties.GQ262 efficiently blocked UM cell proliferation and migration in vitro.Analysis of the apoptosis-related proteins,extracel-lular signal-regulated kinase(ERK),and yes-associated protein(YAP)demonstrated that GQ262 distinctly induced UM cells apoptosis and disrupted the downstream effectors by targeting Gαq/11 directly.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 Gαq/11 may be an efficient strategy against uveal melanoma.