A Nanomolar-Potency Small Molecule Inhibitor of Regulator of G-Protein Signaling Proteins

Blazer, Levi L.; Zhang, Haoming; Casey, Emma M.; Husbands, Stephen M.; Neubig, Richard R.

doi:10.1021/bi1019622

Cited by 65 publications

(135 citation statements)

References 30 publications

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“…Like CCG-4986, CCG-63802 showed selectivity for RGS4 over other RGS proteins studied. A third series of small molecule RGS4 inhibitors is represented by CCG-50014, which is the first RGS inhibitor that has shown activity in cells (Blazer et al, 2011). A derivative of CCG-50014, CCG-203769, was also demonstrated to have effects in vivo.…”

Section: Advances In Rgs Protein Drug Discovery -From Biochemical Actmentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.Abbreviations DEP, Disheveled Egl-10 Pleckstrin; GAP, GTPase-activating protein; GGL, G protein γ-like; PPI, protein-protein interaction; RGS, regulator of G protein signalling; R7BP, R7 binding protein; R9AP, RGS9 associated protein IntroductionG protein-mediated signalling pathways have played a pivotal role in drug discovery and development for many decades. The large family of GPCRs or their downstream effectors are the target of 40% of clinically used drugs and thus represent a multi-billion-dollar industry (Wise et al., 2002). Interestingly, of the more than 300 non-olfactory GPCRs known, only a fraction of them are targeted by drugs. Thus, there is a large untapped area of drug development still available. Moreover, many GPCR drugs are associated with low efficacy and/or side effects. More targeted therapies are therefore required, and as we learn more about the structure and function of GPCRs and their regulators, these goals will be achievable.All biological signals are tightly regulated and for every on-switch there is usually an off-switch. GPCRs are activated by ligands, transmitting signalling information to Gα subunits of heterotrimeric G proteins by enhancing the exchange of GDP for GTP in the Gα nucleotide binding site, which results in the dissociation of Gα from Gβγ dimers and activation of both G protein components. Deactivation of G proteins does not occur by simple reversal of nucleotide exchange, but rather by an independently regulated GTPase activity, hydrolyzing GTP to GDP. Although Gα proteins possess an intrinsic ability to hydrolyze GTP, this process is very slow and cannot account for the transient nature of intracellular signalling cascades in vivo. Hence, additional kinetic mechanisms are required for the physiological timing of signals. One of the most critical of these kinetic mechanisms is mediated through regulator of G protein signalling (RGS) proteins, which have received increasing interest as novel drug targets in the past two decades. As a result, RGS proteins have now been added as the most recent ad...

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Section: Advances In Rgs Protein Drug Discovery -From Biochemical Actmentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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“…Modulation of RGS proteins might alter GPCR signaling in a pathway-and tissue-specific manner (Blazer and Neubig, 2009). Although RGS proteins are considered to be difficult drug targets (Tesmer et al, 1997), we and others have made significant progress in developing RGS protein inhibitors (Roman et al, 2007;Blazer et al, 2010Blazer et al, , 2011Turner et al, 2012). In other cases, however, increasing RGS protein function may be therapeutically beneficial.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, we (Zhong and Neubig, 2001; and others (Doggrell, 2004;Riddle et al, 2005;da Costa Goncalves et al, 2008) suggested that RGS proteins, including RGS2, might represent novel cardiovascular therapeutic targets. Although significant progress has been made in identifying RGS inhibitors (Blazer et al, 2011;Turner et al, 2012), enhancing RGS action is more challenging .…”

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confidence: 99%

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

et al. 2012

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Regulator of G protein signaling 2 (RGS2), a G q -specific GTPase-activating protein, is strongly implicated in cardiovascular function. RGS2(Ϫ/Ϫ) mice are hypertensive and prone to heart failure, and several rare human mutations that accelerate RGS2 degradation have been identified among patients with hypertension. Therefore, pharmacological up-regulation of RGS2 protein levels might be beneficial. We used a ␤-galactosidase complementation method to screen several thousand compounds with known pharmacological functions for those that increased RGS2 protein levels. Several cardiotonic steroids (CTSs), including ouabain and digoxin, increased RGS2 but not RGS4 protein levels. CTSs increased RGS2 protein levels through a post-transcriptional mechanism, by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment, whereas protein levels were increased 2-to 3-fold. Na ϩ /K ϩ -ATPase was required for the increase in RGS2 protein levels, because the effect was lost in Na ϩ /K ϩ -ATPase-knockdown cells. Furthermore, we demonstrated that CTS-induced increases in RGS2 levels were functional and reduced receptor-stimulated, G qdependent, extracellular signal-regulated kinase phosphorylation. Finally, we showed that in vivo treatment with digoxin led to increased RGS2 protein levels in heart and kidney. CTSinduced increases in RGS2 protein levels and function might modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism might contribute to the beneficial actions of low-dose digoxin treatment in heart failure. Our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapy.

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“…This idea has been bolstered by the intriguing phenotypes observed in mice carrying RGS-insensitive Ga mutants, which showed that blocking RGS actions potentiates neurotransmitter actions and linked behaviors in a targeted fashion (Talbot et al, 2010;Lamberts et al, 2013). While initial efforts focused on the identification and development of peptide inhibitors of RGS proteins as proof of concept (Jin et al, 2004;Wang et al, 2008), more recent work has focused on the development of small molecule inhibitors with the goal of treating multiple diseases, including neurologic disorders (Blazer et al, , 2011Roman and Traynor, 2011;Turner et al, 2012;Storaska et al, 2013). Thus far, RGS4 has been the main focus for the development of small molecule RGS inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

2015

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The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Ga subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre-and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9-2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets.

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A Nanomolar-Potency Small Molecule Inhibitor of Regulator of G-Protein Signaling Proteins

Cited by 65 publications

References 30 publications

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

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