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

作　　者：Yang Ge Jun-Jie Deng Jianzheng Zhu Lu Liu Shumin Ouyang Zhendong Song Xiaolei Zhang Xiao-Feng Xiong 

机构地区：[1]National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation,Guangdong Province Engineering Laboratory for Druggability and New Drugs Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第8期3326-3340,共15页药学学报（英文版）

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);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)。

摘　　要：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.

关 键 词：G proteins Gaq/11 inhibitors SARS BRET Uveal melanoma ANTITUMOR Safety PHARMACOKINETICS 

分 类 号：R739.7[医药卫生—肿瘤]