TY  - JOUR
AU  - Zhao, Jingyi
AU  - DiGiacomo, Vincent
AU  - Ferreras-Gutierrez, Mariola
AU  - Dastjerdi, Shiva
AU  - Ibanez de Opakua, Alain
AU  - Park, Jong-Chan
AU  - Luebbers, Alex
AU  - Chen, Qingyan
AU  - Beeler, Aaron
AU  - Blanco, Francisco J
AU  - Garcia-Marcos, Mikel
TI  - Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 120
IS  - 18
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DZNE-2023-00494
SP  - e2213140120
PY  - 2023
AB  - 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.
KW  - Vesicular Transport Proteins: metabolism
KW  - Microfilament Proteins: metabolism
KW  - Signal Transduction
KW  - Receptors, G-Protein-Coupled: metabolism
KW  - Heterotrimeric GTP-Binding Proteins: metabolism
KW  - Neoplasms: metabolism
KW  - G protein (Other)
KW  - GPCR (Other)
KW  - cancer (Other)
KW  - drug discovery (Other)
KW  - Vesicular Transport Proteins (NLM Chemicals)
KW  - Microfilament Proteins (NLM Chemicals)
KW  - Receptors, G-Protein-Coupled (NLM Chemicals)
KW  - Heterotrimeric GTP-Binding Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC10160980
C6  - pmid:37098067
DO  - DOI:10.1073/pnas.2213140120
UR  - https://pub.dzne.de/record/257779
ER  -