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Synthesis and evaluation of imidazo[1,2-a]pyrazine derivatives as small molecule Gαq/11 inhibitors against uveal melanoma
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-06-11 , 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 1
Affiliation  

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.



中文翻译:

咪唑并[1,2-a]吡嗪衍生物作为葡萄膜黑色素瘤小分子Gαq/11抑制剂的合成与评价

葡萄膜黑色素瘤 (UM) 是一种侵袭性恶性肿瘤,成人死亡率高,缺乏有效的全身治疗。与 Gαq/11 信号通路相关的激活基因突变在 UM 中普遍存在,Gαq/11 抑制剂在体外体内均显示出抗 UM 活性。本研究设计合成了一系列咪唑并[1,2- a ]吡嗪衍生物作为Gαq/11抑制剂,发现GQ352对UM细胞具有选择性抗增殖活性。重要的是,GQ352直接与 Gαq 结合并抑制 Gαβγ 异源三聚体的解离,IC 50值为 8.9 μM。GQ352如蛋白质印迹分析所示,通过抑制 Gαq/11 下游 ERK 磷酸化和 YAP 去磷酸化来抑制 UM 肿瘤发生。此外,GQ352表现出合理的理化性质和人肝微粒体稳定性,表明在UM治疗中的潜在应用。

更新日期:2022-06-16
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