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@ARTICLE{Zhao:257779,
      author       = {Zhao, Jingyi and DiGiacomo, Vincent and Ferreras-Gutierrez,
                      Mariola and Dastjerdi, Shiva and Ibanez de Opakua, Alain and
                      Park, Jong-Chan and Luebbers, Alex and Chen, Qingyan and
                      Beeler, Aaron and Blanco, Francisco J and Garcia-Marcos,
                      Mikel},
      title        = {{S}mall-molecule targeting of {GPCR}-independent
                      noncanonical {G}-protein signaling in cancer.},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {120},
      number       = {18},
      issn         = {0027-8424},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {DZNE-2023-00494},
      pages        = {e2213140120},
      year         = {2023},
      abstract     = {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.},
      keywords     = {Vesicular Transport Proteins: metabolism / Microfilament
                      Proteins: metabolism / Signal Transduction / Receptors,
                      G-Protein-Coupled: metabolism / Heterotrimeric GTP-Binding
                      Proteins: metabolism / Neoplasms: metabolism / G protein
                      (Other) / GPCR (Other) / cancer (Other) / drug discovery
                      (Other) / Vesicular Transport Proteins (NLM Chemicals) /
                      Microfilament Proteins (NLM Chemicals) / Receptors,
                      G-Protein-Coupled (NLM Chemicals) / Heterotrimeric
                      GTP-Binding Proteins (NLM Chemicals)},
      cin          = {AG Zweckstetter},
      ddc          = {500},
      cid          = {I:(DE-2719)1410001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC10160980},
      pubmed       = {pmid:37098067},
      doi          = {10.1073/pnas.2213140120},
      url          = {https://pub.dzne.de/record/257779},
}