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001     257779
005     20231004170001.0
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024 7 _ |a 10.1073/pnas.2213140120
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037 _ _ |a DZNE-2023-00494
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Zhao, Jingyi
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245 _ _ |a Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.
260 _ _ |a Washington, DC
|c 2023
|b National Acad. of Sciences
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520 _ _ |a 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.
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650 _ 7 |a G protein
|2 Other
650 _ 7 |a GPCR
|2 Other
650 _ 7 |a cancer
|2 Other
650 _ 7 |a drug discovery
|2 Other
650 _ 7 |a Vesicular Transport Proteins
|2 NLM Chemicals
650 _ 7 |a Microfilament Proteins
|2 NLM Chemicals
650 _ 7 |a Receptors, G-Protein-Coupled
|2 NLM Chemicals
650 _ 7 |a Heterotrimeric GTP-Binding Proteins
|0 EC 3.6.5.1
|2 NLM Chemicals
650 _ 2 |a Vesicular Transport Proteins: metabolism
|2 MeSH
650 _ 2 |a Microfilament Proteins: metabolism
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a Receptors, G-Protein-Coupled: metabolism
|2 MeSH
650 _ 2 |a Heterotrimeric GTP-Binding Proteins: metabolism
|2 MeSH
650 _ 2 |a Neoplasms: metabolism
|2 MeSH
700 1 _ |a DiGiacomo, Vincent
|b 1
700 1 _ |a Ferreras-Gutierrez, Mariola
|0 0000-0003-4421-3158
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700 1 _ |a Dastjerdi, Shiva
|b 3
700 1 _ |a Ibanez de Opakua, Alain
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700 1 _ |a Park, Jong-Chan
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700 1 _ |a Luebbers, Alex
|b 6
700 1 _ |a Chen, Qingyan
|b 7
700 1 _ |a Beeler, Aaron
|b 8
700 1 _ |a Blanco, Francisco J
|0 0000-0003-2545-4319
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700 1 _ |a Garcia-Marcos, Mikel
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773 _ _ |a 10.1073/pnas.2213140120
|g Vol. 120, no. 18, p. e2213140120
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|t Proceedings of the National Academy of Sciences of the United States of America
|v 120
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