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

Authors :
Yang Ge
Jun-Jie Deng
Jianzheng Zhu
Lu Liu
Shumin Ouyang
Zhendong Song
Xiaolei Zhang
Xiao-Feng Xiong
Source :
Acta Pharmaceutica Sinica B, Vol 12, Iss 8, Pp 3326-3340 (2022)
Publication Year :
2022
Publisher :
Elsevier, 2022.

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.

Details

Language :
English
ISSN :
22113835
Volume :
12
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Acta Pharmaceutica Sinica B
Publication Type :
Academic Journal
Accession number :
edsdoj.6f4dc81eff04094b80f1911d7388606
Document Type :
article
Full Text :
https://doi.org/10.1016/j.apsb.2022.04.016