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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.

Citation

Yang Ge, Shuo Shi, Jun-Jie Deng, Xue-Ping Chen, Zhendong Song, Lu Liu, Linlin Lou, Xiaolei Zhang, Xiao-Feng Xiong. Design, Synthesis, and Evaluation of Small Molecule Gαq/11 Protein Inhibitors for the Treatment of Uveal Melanoma. Journal of medicinal chemistry. 2021 Mar 25;64(6):3131-3152


PMID: 33715360

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