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000257779 037__ $$aDZNE-2023-00494
000257779 041__ $$aEnglish
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000257779 1001_ $$00000-0002-3125-2716$$aZhao, Jingyi$$b0
000257779 245__ $$aSmall-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.
000257779 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2023
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000257779 520__ $$aActivation 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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000257779 650_7 $$2Other$$aG protein
000257779 650_7 $$2Other$$aGPCR
000257779 650_7 $$2Other$$acancer
000257779 650_7 $$2Other$$adrug discovery
000257779 650_7 $$2NLM Chemicals$$aVesicular Transport Proteins
000257779 650_7 $$2NLM Chemicals$$aMicrofilament Proteins
000257779 650_7 $$2NLM Chemicals$$aReceptors, G-Protein-Coupled
000257779 650_7 $$0EC 3.6.5.1$$2NLM Chemicals$$aHeterotrimeric GTP-Binding Proteins
000257779 650_2 $$2MeSH$$aVesicular Transport Proteins: metabolism
000257779 650_2 $$2MeSH$$aMicrofilament Proteins: metabolism
000257779 650_2 $$2MeSH$$aSignal Transduction
000257779 650_2 $$2MeSH$$aReceptors, G-Protein-Coupled: metabolism
000257779 650_2 $$2MeSH$$aHeterotrimeric GTP-Binding Proteins: metabolism
000257779 650_2 $$2MeSH$$aNeoplasms: metabolism
000257779 7001_ $$aDiGiacomo, Vincent$$b1
000257779 7001_ $$00000-0003-4421-3158$$aFerreras-Gutierrez, Mariola$$b2
000257779 7001_ $$aDastjerdi, Shiva$$b3
000257779 7001_ $$0P:(DE-2719)2812657$$aIbanez de Opakua, Alain$$b4$$udzne
000257779 7001_ $$aPark, Jong-Chan$$b5
000257779 7001_ $$aLuebbers, Alex$$b6
000257779 7001_ $$aChen, Qingyan$$b7
000257779 7001_ $$aBeeler, Aaron$$b8
000257779 7001_ $$00000-0003-2545-4319$$aBlanco, Francisco J$$b9
000257779 7001_ $$00000-0001-9513-4826$$aGarcia-Marcos, Mikel$$b10
000257779 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.2213140120$$gVol. 120, no. 18, p. e2213140120$$n18$$pe2213140120$$tProceedings of the National Academy of Sciences of the United States of America$$v120$$x0027-8424$$y2023
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