Journal Article

DZNE-2023-00494

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.

Zhao, J. ; DiGiacomo, V. ; Ferreras-Gutierrez, M. ; Dastjerdi, S. ; Ibanez de Opakua, A.DZNE* ; Park, J.-C. ; Luebbers, A. ; Chen, Q. ; Beeler, A. ; Blanco, F. J. ; Garcia-Marcos, M.

2023
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: doi:10.1073/pnas.2213140120

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.

Keyword(s): 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) ; G protein ; GPCR ; cancer ; drug discovery ; Vesicular Transport Proteins ; Microfilament Proteins ; Receptors, G-Protein-Coupled ; Heterotrimeric GTP-Binding Proteins

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Contributing Institute(s):

1. Structural Biology in Dementia (AG Zweckstetter)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; National-Konsortium ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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