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...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.展开更多
基金financial support by National Natural Science Foundation of China (No.22077144 and 81973359)Guangdong Natural Science Funds for Distinguished Young Scholar (No.2018B030306017,China)+4 种基金Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery (2019B030301005,China)Key Reasearch and Development Program of Guangdong Province (2020B1111110003,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093,China)National Engineering and Technology Research Center for New Drug Druggability Evaluation (Seed Program of Guangdong Province,2017B090903004)Jilin Province Science and Technology Development Project (20200404105YY)。
文摘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.
