Synthesis and evaluation of imidazo[1,2-a]pyrazine derivatives as small molecule Gαq/11 inhibitors against uveal melanoma

Jun-Jie Deng; Lu Liu; Yang Ge; Zhendong Song; Jie Huang; Guangjin Fan; Xiao-Feng Xiong

doi:10.1016/j.ejmech.2022.114520

Synthesis and evaluation of imidazo[1,2-a]pyrazine derivatives as small molecule Gαq/11 inhibitors against uveal melanoma

Eur J Med Chem. 2022 Sep 5:239:114520. doi: 10.1016/j.ejmech.2022.114520. Epub 2022 Jun 11.

Authors

Jun-Jie Deng¹, Lu Liu¹, Yang Ge¹, Zhendong Song¹, Jie Huang², Guangjin Fan¹, Xiao-Feng Xiong³

Affiliations

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, 510006, Guangzhou, Guangdong, PR China.
² Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
³ 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, 510006, Guangzhou, Guangdong, PR China. Electronic address: [email protected].

PMID: 35716516
DOI: 10.1016/j.ejmech.2022.114520

Abstract

Uveal melanoma (UM) is an aggressive malignancy with high mortality in adults and lacks effective systemic therapies. Activating gene mutations related to the Gαq/11 signaling pathway are prevalent in UM, and Gαq/11 inhibitors have shown anti-UM activity in vitro and in vivo. In this study, we designed and synthesized a series of imidazo[1,2-a]pyrazine derivatives as Gαq/11 inhibitors, and discovered GQ352 with the selective antiproliferative activity against UM cells. Importantly, GQ352 directly binds to the Gαq and inhibits the dissociation of Gαβγ heterotrimers with the IC₅₀ value of 8.9 μM. GQ352 inhibits UM tumorigenesis by suppressing Gαq/11 downstream ERK phosphorylation and YAP dephosphorylation, as shown in Western blot analysis. In addition, GQ352 displayed reasonable physiochemical properties and human liver microsome stability, indicating the potential application in UM treatment.

Keywords: Antitumor; G proteins; Gαq/11 inhibitors; Uveal melanoma; imidazo[1,2-a]pyrazine.

MeSH terms

Cell Line, Tumor
Humans
Melanoma* / metabolism
Pyrazines / pharmacology
Uveal Neoplasms* / drug therapy
Uveal Neoplasms* / genetics
Uveal Neoplasms* / metabolism

Substances

Pyrazines

Supplementary concepts

Uveal melanoma