Announcing a new article publication from Acta Pharmaceutica Sinica B. 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.
In this article, the authors 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.
These findings along with the favorable pharmacokinetics of GQ262 suggest that directly targeting Gαq/11 may be an efficient strategy against uveal melanoma.
Article reference: Yang Ge, Jun-Jie Deng, Jianzheng Zhu, Lu Liu, Shumin Ouyang, Zhendong Song, Xiaolei Zhang, Xiao-Feng Xiong, Discovery of small molecule Gαq/11 protein inhibitors against uveal melanoma, Acta Pharmaceutica Sinica B, Volume 12, Issue 8, 2022, Pages 3326-3340, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2022.04.016.
Keywords: G proteins, Gαq/11 inhibitors, SARs, BRET, Uveal melanoma, Antitumor Safety, Pharmacokinetics
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383522002040-ga1_lrg.jpg
Constitutively activated Gαq/11 proteins drive the vast majority of uveal melanoma (UM). GQ262 effectively combats UM both in vitro and in vivo by targeting Gαq/11 directly.
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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.
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Acta Pharmaceutica Sinica B