engZhao, JingyiDiGiacomo, VincentGarcia-Marcos, MikelFerreras-Gutierrez, MariolaDastjerdi, ShivaIbanez de Opakua, AlainPark, Jong-ChanLuebbers, AlexChen, QingyanBeeler, AaronBlanco, Francisco JSmall-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.info:eu-repo/classification/ddc/500Vesicular Transport Proteins: metabolismMicrofilament Proteins: metabolismSignal TransductionReceptors, G-Protein-Coupled: metabolismHeterotrimeric GTP-Binding Proteins: metabolismNeoplasms: metabolismG proteinGPCRcancerdrug discoveryVesicular Transport ProteinsMicrofilament ProteinsReceptors, G-Protein-CoupledHeterotrimeric GTP-Binding ProteinsActivation 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.Proceedings of the National Academy of Sciences of the United States of America 120(18), e2213140120 (2023). doi:10.1073/pnas.2213140120info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionNational Acad. of Sciences2023info:eu-repo/semantics/openAccessDEhttps://pub.dzne.de/record/257779https://pub.dzne.de/search?p=id:%22DZNE-2023-00494%22Researchersinfo:eu-repo/semantics/altIdentifier/issn/0027-8424info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.2213140120info:eu-repo/semantics/altIdentifier/pmid/pmid:37098067info:eu-repo/semantics/altIdentifier/issn/1091-6490