%0 Journal Article
%A Zhao, Jingyi
%A DiGiacomo, Vincent
%A Ferreras-Gutierrez, Mariola
%A Dastjerdi, Shiva
%A Ibanez de Opakua, Alain
%A Park, Jong-Chan
%A Luebbers, Alex
%A Chen, Qingyan
%A Beeler, Aaron
%A Blanco, Francisco J
%A Garcia-Marcos, Mikel
%T Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.
%J Proceedings of the National Academy of Sciences of the United States of America
%V 120
%N 18
%@ 0027-8424
%C Washington, DC
%I National Acad. of Sciences
%M DZNE-2023-00494
%P e2213140120
%D 2023
%X 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.
%K Vesicular Transport Proteins: metabolism
%K Microfilament Proteins: metabolism
%K Signal Transduction
%K Receptors, G-Protein-Coupled: metabolism
%K Heterotrimeric GTP-Binding Proteins: metabolism
%K Neoplasms: metabolism
%K G protein (Other)
%K GPCR (Other)
%K cancer (Other)
%K drug discovery (Other)
%K Vesicular Transport Proteins (NLM Chemicals)
%K Microfilament Proteins (NLM Chemicals)
%K Receptors, G-Protein-Coupled (NLM Chemicals)
%K Heterotrimeric GTP-Binding Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%2 pmc:PMC10160980
%$ pmid:37098067
%R 10.1073/pnas.2213140120
%U https://pub.dzne.de/record/257779