Discovery of small molecule Gαq/11 protein inhibitors against uveal melanoma
Yang Ge1, Jun-Jie Deng1, Jianzheng Zhu1
1National-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.
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.
Insights
Researchers optimized imidazopiperazine derivatives to create GQ262, a novel Gαq/11 inhibitor. This compound effectively inhibited uveal melanoma cell growth and migration, offering a promising targeted therapy for this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Mutations in Gαq/11 proteins are key drivers in many cancers, particularly uveal melanoma (UM).
- Targeting these mutated Gαq/11 proteins presents a potential therapeutic strategy for UM.
Purpose of the Study:
- To optimize imidazopiperazine derivatives for inhibiting Gαq/11.
- To evaluate the efficacy and safety of the lead compound, GQ262, against uveal melanoma.
Main Methods:
- Optimization of imidazopiperazine derivatives to identify potent Gαq/11 inhibitors.
- In vitro studies assessing GQ262's effects on UM cell proliferation, migration, and apoptosis.
- In vivo studies evaluating GQ262's antitumor efficacy and safety in a preclinical model.
Main Results:
- GQ262 demonstrated improved Gαq/11 inhibitory activity and favorable drug-like properties.
- GQ262 effectively inhibited UM cell proliferation and migration in vitro.
- GQ262 induced apoptosis in UM cells by targeting Gαq/11 and disrupting downstream signaling pathways (ERK, YAP).
- GQ262 exhibited significant antitumor efficacy and good safety in vivo.
Conclusions:
- Directly targeting Gαq/11 with inhibitors like GQ262 is a viable and promising strategy for treating uveal melanoma.
- GQ262 shows potential as a therapeutic agent for uveal melanoma due to its efficacy and favorable pharmacokinetic profile.
