化学
脱磷
吡嗪
磷酸化
体内
IC50型
黑色素瘤
丝氨酸
体外
免疫印迹
癌症研究
立体化学
分子生物学
生物化学
基因
磷酸酶
生物技术
生物
作者
Junjie Deng,Lu Liu,Ge Yang,Zhendong Song,Jie Huang,Guangjin Fan,X. Xiong
标识
DOI:10.1016/j.ejmech.2022.114520
摘要
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.
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