Discovery of small molecule Gαq/11 protein inhibitors against uveal melanoma.
10.1016/j.apsb.2022.04.016
- Author:
Yang GE
1
;
Jun-Jie DENG
1
;
Jianzheng ZHU
1
;
Lu LIU
1
;
Shumin OUYANG
1
;
Zhendong SONG
1
;
Xiaolei ZHANG
1
;
Xiao-Feng XIONG
1
Author Information
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.
- Publication Type:Journal Article
- Keywords:
Antitumor;
BRET;
G proteins;
Gαq/11 inhibitors;
Pharmacokinetics;
SARs;
Safety;
Uveal melanoma
- From:
Acta Pharmaceutica Sinica B
2022;12(8):3326-3340
- CountryChina
- Language:English
-
Abstract:
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.
