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

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.
Jun-Jie Deng 1,  Lu Liu 1,  Yang Ge 1,  Zhendong Song 1,  Jie Huang 2,  Guangjin Fan 1,  Xiao-Feng Xiong 3
Affiliations

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.

Figures