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

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.