257779 20231004170001.0 pmc:PMC10160980 pmc 10.1073/pnas.2213140120 doi pmid:37098067 pmid 0027-8424 ISSN 1091-6490 ISSN altmetric:146672791 altmetric DZNE-2023-00494 English 500 Zhao, Jingyi 0000-0002-3125-2716 0 Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer. Washington, DC 2023 National Acad. of Sciences article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1685610591_8126 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de 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 EC 3.6.5.1 NLM Chemicals Vesicular Transport Proteins: metabolism MeSH Microfilament Proteins: metabolism MeSH Signal Transduction MeSH Receptors, G-Protein-Coupled: metabolism MeSH Heterotrimeric GTP-Binding Proteins: metabolism MeSH Neoplasms: metabolism MeSH DiGiacomo, Vincent 1 Ferreras-Gutierrez, Mariola 0000-0003-4421-3158 2 Dastjerdi, Shiva 3 Ibanez de Opakua, Alain P:(DE-2719)2812657 4 dzne Park, Jong-Chan 5 Luebbers, Alex 6 Chen, Qingyan 7 Beeler, Aaron 8 Blanco, Francisco J 0000-0003-2545-4319 9 Garcia-Marcos, Mikel 0000-0001-9513-4826 10 10.1073/pnas.2213140120 Vol. 120, no. 18, p. e2213140120 PERI:(DE-600)1461794-8 18 e2213140120 Proceedings of the National Academy of Sciences of the United States of America 120 2023 0027-8424 http://pub.dzne.de/record/257779/files/DZNE-2023-00494%20SUP.pdf OpenAccess http://pub.dzne.de/record/257779/files/DZNE-2023-00494.pdf pdfa http://pub.dzne.de/record/257779/files/DZNE-2023-00494%20SUP.pdf?subformat=pdfa OpenAccess pdfa http://pub.dzne.de/record/257779/files/DZNE-2023-00494.pdf?subformat=pdfa oai:pub.dzne.de:257779 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 4 P:(DE-2719)2812657 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2023 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2022-11-08 Creative Commons Attribution-NonCommercial-NoDerivs CC BY-NC-ND 4.0 LIC:(DE-HGF)CCBYNCND4 HGFVOC WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2022-11-08 OpenAccess StatID:(DE-HGF)0510 StatID DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2022-11-08 National-Konsortium StatID:(DE-HGF)0430 StatID 2023-08-26 ger JCR StatID:(DE-HGF)0100 StatID P NATL ACAD SCI USA : 2022 2023-08-26 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2023-08-26 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2023-08-26 DBCoverage StatID:(DE-HGF)0320 StatID PubMed Central 2023-08-26 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2023-08-26 Peer Review StatID:(DE-HGF)0030 StatID ASC 2023-08-26 DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2023-08-26 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2023-08-26 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2023-08-26 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2023-08-26 DBCoverage StatID:(DE-HGF)1060 StatID Current Contents - Agriculture, Biology and Environmental Sciences 2023-08-26 DBCoverage StatID:(DE-HGF)1040 StatID Zoological Record 2023-08-26 IF >= 10 StatID:(DE-HGF)9910 StatID P NATL ACAD SCI USA : 2022 2023-08-26 I:(DE-2719)1410001 AG Zweckstetter Structural Biology in Dementia 0 journal VDB UNRESTRICTED I:(DE-2719)1410001 FullTexts