Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer

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.

Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk

“…This family of broadly expressed guanine nucleotide exchange factors (GEFs), including proteins like Girdin/GIV and DAPLE, has been shown to drive nucleotide exchange and Gβγ release from G-protein heterotrimers, 57 , 71 - 76 including in response to RTK activation. 56 , 57 , 72 - 74 , 76 , 77 To determine the necessity of direct involvement of G proteins for TrkB to crosstalk with mGluR5, we turned to a previously reported tool, termed GBAi. 78 , 79 This is an engineered synthetic protein based on Gα that binds with high affinity to GBA motifs, but not to other known Gα interactors (i.e., Gβγ, GPCRs, effectors, RGS proteins, Ric-8A, GoLoco motifs), to specifically block GBA-dependent G-protein signaling without interference in canonical signaling via GPCRs ( Figure 5F ).…”

The G Protein-Coupled Estrogen Receptor (GPER): A Critical Therapeutic Target for Cancer

“…From the prevalence of GPCRs in current drug design and the role they play in cancer, it is not surprising that the development of cancer drugs that target GPCRs is gaining traction [141,[147][148][149]. A variety of different treatment strategies are under development, including small molecule pharmacological compounds that target GPCRs and G proteins [150], as well as antibody-based approaches [84]. In 2006, Prossnitz and colleagues developed a small molecule selective GPER agonist, named G-1 [151], that has been instrumental in deciphering the individual molecular signaling activities of GPER, ERα, and ERβ.…”