17 Zhao, Jingyi DiGiacomo, Vincent Ferreras-Gutierrez, Mariola Dastjerdi, Shiva Ibanez de Opakua, Alain Park, Jong-Chan Luebbers, Alex Chen, Qingyan Beeler, Aaron Blanco, Francisco J Garcia-Marcos, Mikel AG Zweckstetter Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America National Acad. of Sciences Washington, DC 0027-8424 10.1073/pnas.2213140120 English e2213140120 18 120 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 small-molecule inhibitor of noncanonical activation of heterotrimeric G-protein signaling. IGGi-11 binding to G-protein α-subunits (Gαi) specifically disrupted their engagement with GIV/Girdin, thereby blocking noncanonical G-protein signaling in tumor cells and inhibiting proinvasive traits of metastatic cancer cells. In contrast, IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs. By revealing that small molecules can selectively disable noncanonical 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. PUB:(DE-HGF)16, ; 0, ; Vesicular Transport Proteins: metabolism Microfilament Proteins: metabolism Signal Transduction Receptors, G-Protein-Coupled: metabolism Heterotrimeric GTP-Binding Proteins: metabolism Neoplasms: metabolism G protein GPCR cancer drug discovery Vesicular Transport Proteins Microfilament Proteins Receptors, G-Protein-Coupled Heterotrimeric GTP-Binding Proteins Journal Article 2023 DZNE-2023-00494 2023 pmc:PMC10160980 pmid:37098067 https://pub.dzne.de/record/257779 https://doi.org/10.1073/pnas.2213140120