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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 identified 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, 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 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.

Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated G α q/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma (UM) cases, making directly targeting G α q/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as G α q/11 inhibitors, and identified GQ262 with improved G α q/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 G α q/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 G α q/11 may be an efficient strategy against uveal melanoma. Constitutively activated G α q/11 proteins drive the vast majority of uveal melanoma (UM). GQ262 effectively combats UM both in vitro and in vivo by targeting G α q/11 directly. [Display omitted] [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is an aggressive malignancy with high mortality in adults and lacks effective systemic therapies. Activating gene mutations related to the Gαq/11 signaling pathway are prevalent in UM, and Gαq/11 inhibitors have shown anti-UM activity in vitro and in vivo. In this study, we designed and synthesized a series of imidazo[1,2- a ]pyrazine derivatives as Gαq/11 inhibitors, and discovered GQ352 with the selective antiproliferative activity against UM cells. Importantly, GQ352 directly binds to the Gαq and inhibits the dissociation of Gαβγ heterotrimers with the IC 50 value of 8.9 μM. GQ352 inhibits UM tumorigenesis by suppressing Gαq/11 downstream ERK phosphorylation and YAP dephosphorylation, as shown in Western blot analysis. In addition, GQ352 displayed reasonable physiochemical properties and human liver microsome stability, indicating the potential application in UM treatment. [Display omitted] • Systematic structure-activity relationship was explored on 45 imidazo[1,2- a ]pyrazine derivatives. • Compound GQ352 displayed selective antiproliferative activity against UM cells with mutant Gαq/11 proteins. • GQ352 displayed inhibitory potency on G proteins by direct binding to the Gαq/11 subunit. • GQ352 showed reasonable physiochemical properties and human liver microsome stability. [ABSTRACT FROM AUTHOR]

Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated G α q/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma (UM) cases, making directly targeting G α q/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as G α q/11 inhibitors, and identified GQ262 with improved G α q/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 G α q/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 G α q/11 may be an efficient strategy against uveal melanoma., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)