Discovery of small molecule Gαq/11 protein inhibitors against uveal melanoma
© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Acta pharmaceutica Sinica. B - 12(2022), 8 vom: 03. Aug., Seite 3326-3340 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ge, Yang [VerfasserIn] |
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| Links: |
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| Themen: |
Antitumor |
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| Anmerkungen: |
Date Revised 16.08.2022 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.apsb.2022.04.016 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM344860043 |
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| 520 | |a 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 | ||
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| 650 | 4 | |a Gαq/11 inhibitors | |
| 650 | 4 | |a Pharmacokinetics | |
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| 700 | 1 | |a Deng, Jun-Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Jianzheng |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Ouyang, Shumin |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Zhendong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaolei |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Xiao-Feng |e verfasserin |4 aut | |
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