Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression.
Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression.
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小分子靶向不依赖于 GPCR 的非经典 G 蛋白信号传导可抑制癌症进展。
DOI：
10.1101/2023.02.18.529092
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Garcia-Marcos,Mikel
中科院分区：
文献类型：
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作者：
Zhao,Jingyi;DiGiacomo,Vincent;Ferreras-Gutierrez,Mariola;Dastjerdi,Shiva;deOpakua,AlainIbáñez;Park,Jong-Chan;Luebbers,Alex;Chen,Qingyan;Beeler,Aaron;Blanco,FranciscoJ;Garcia-Marcos,Mikel
g蛋白偶联受体（gpcr）激活异三聚体g蛋白（Gαβγ）是临床批准的药物广泛靶向的细胞信号传导的典型机制。然而，很明显，异三聚体g蛋白也可以通过不依赖gpcr的机制被激活，这些机制作为药理学靶点尚未开发。GIV/Girdin已成为促进癌症转移的G蛋白的典型非gpcr激活剂。在这里，我们介绍了IGGi-11，这是一种非典型激活异三聚体g蛋白信号的小分子抑制剂。IGGi-11与g蛋白α-亚基（Gαi）的结合特异性地破坏了它们与GIV/Girdin的结合，从而阻断肿瘤细胞中的非规范g蛋白信号，并抑制小鼠体外转移癌细胞的前侵袭特性。相反，IGGi-11不干扰由gpcr触发的典型g蛋白信号机制。通过揭示小分子可以选择性地禁用疾病中失调的g蛋白激活的非规范机制，这些发现为探索超越靶向gpcr的g蛋白信号的治疗方式提供了依据。
Activation of heterotrimeric G-proteins (Gαβγ) by G-protein-coupled receptors (GPCRs) is a quintessential mechanism of cell signaling widely targeted by clinically-approved drugs. However, it has become evident that heterotrimeric G-proteins can also be activated via GPCR-independent mechanisms that remain untapped as pharmacological targets. GIV/Girdin has emerged as a prototypical non-GPCR activator of G proteins that promotes cancer metastasis. Here, we introduce IGGi-11, a first-in-class smallmolecule inhibitor of non-canonical activation of heterotrimeric G-protein signaling. IGGi-11 binding to G-protein α-subunits (Gαi) specifically disrupted their engagement with GIV/Girdin, thereby blocking non-canonical G-protein signaling in tumor cells, and inhibiting pro-invasive traits of metastatic cancer cellsin vitroand in mice. In contrast, IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs. By revealing that small molecules can selectively disable non-canonical mechanisms of G-protein activation dysregulated in disease, these findings warrant the exploration of therapeutic modalities in G-protein signaling that go beyond targeting GPCRs.