6479-48-7Relevant academic research and scientific papers
Design, Synthesis, and Evaluation of Small Molecule Gαq/11 Protein Inhibitors for the Treatment of Uveal Melanoma
Ge, Yang,Shi, Shuo,Deng, Jun-Jie,Chen, Xue-Ping,Song, Zhendong,Liu, Lu,Lou, Linlin,Zhang, Xiaolei,Xiong, Xiao-Feng
, p. 3131 - 3152 (2021)
Uveal melanoma is the ocular malignancy and mainly driven by oncogenic mutations of Gαq/11 proteins. Previous targeted therapy for melanoma treatment was limited to specific downstream signaling pathway, and inhibiting the "molecular switches"G proteins for melanoma treatment therapy was rarely described. We herein report the discovery of imidazopiperazine derivatives as Gαq/11 protein inhibitors. The most promising compound GQ127 showed good efficacy and safety in inositol monophosphate (IP1) assay by directly inhibiting Gαq/11 proteins. GQ127 induced uveal melanoma cells apoptosis and displayed potent antitumor activities in uveal melanoma cells viability, migration, and invasion. The effects of GQ127 on Gαq/11 signaling pathway were confirmed by analyzing the downstream effectors yes-associated protein (YAP) and extracellular signal-regulated kinase (ERK). More importantly, GQ127 significantly suppressed UM xenograft growth in mouse model without severe toxicity at the testing dose. These findings provide a lead compound that directly targets the Gαq/11 proteins for uveal melanoma treatment.
