Allosteric Inhibition of the Regulator of G Protein Signaling–Gα Protein–Protein Interaction by CCG-4986

Roman, David L.; Blazer, Levi L.; Monroy, C. Aaron; Neubig, Richard R.

doi:10.1124/mol.109.063388

Cited by 45 publications

(91 citation statements)

References 34 publications

(40 reference statements)

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“…For the mutagenesis studies, ⌬N51RGS4 (rat) wild type and cysteine 3 alanine mutants were expressed from the pMALC2H10 vector. Mutagenesis was performed as described elsewhere (Roman et al, 2010) using the QuikChange multi site-directed mutagenesis kit (Stratagene, La Jolla, CA) where one or more of the cysteine residues in the RGS domain of RGS4 were mutated to alanine.…”

Section: Methodsmentioning

confidence: 99%

“…Because of the physical properties of the peptides, none of them function in a cellular environment unless they are introduced intracellularly [e.g., by dialysis via a patch pipette (Roof et al, 2006)]. The small-molecule compound sulfonyl]-4-nitrobenzenesulfinimidoate] irreversibly inhibits RGS4 by reacting with one or more cysteine residues (Kimple et al, 2007;Roman et al, 2010), and its activity is lost in the presence of free thiols. This mechanism of action makes CCG-4986 less desirable as a potential lead compound for small-molecule probe development.…”

Section: Introductionmentioning

confidence: 99%

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Reversible, Allosteric Small-Molecule Inhibitors of Regulator of G Protein Signaling Proteins

Blazer¹,

Roman²,

Chung³

et al. 2010

Mol Pharmacol

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Regulators of G protein signaling (RGS) proteins are potent negative modulators of G protein signaling and have been proposed as potential targets for small-molecule inhibitor development. We report a high-throughput time-resolved fluorescence resonance energy transfer screen to identify inhibitors of RGS4 and describe the first reversible small-molecule inhibitors of an RGS protein. Two closely related compounds, typified by CCG-63802 [((, inhibit the interaction between RGS4 and G␣ o with an IC 50 value in the low micromolar range. They show selectivity among RGS proteins with a potency order of RGS 4 Ͼ 19 ϭ 16 Ͼ 8 Ͼ Ͼ 7. The compounds inhibit the GTPase accelerating protein activity of RGS4, and thermal stability studies demonstrate binding to the RGS but not to G␣ o . On RGS4, they depend on an interaction with one or more cysteines in a pocket that has previously been identified as an allosteric site for RGS regulation by acidic phospholipids. Unlike previous small-molecule RGS inhibitors identified to date, these compounds retain substantial activity under reducing conditions and are fully reversible on the 10-min time scale. CCG-63802 and related analogs represent a useful step toward the development of chemical tools for the study of RGS physiology.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reversible, Allosteric Small-Molecule Inhibitors of Regulator of G Protein Signaling Proteins

Blazer¹,

Roman²,

Chung³

et al. 2010

Mol Pharmacol

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“…Interestingly, screening against RGS4 has often identified cysteine-reactive compounds that bind covalently to a site distinct from the A site (72,73). This site is closer to a region that has been termed the B site that binds endogenous phospholipids to regulate GAP activity, establishing the hypothesis that inhibition of the RGS-Gα PPI can be achieved through molecules that act allosterically to the actual interaction interface (74,75).…”

Section: Chemical Inhibition Of Rgs Proteins Rgs-gα Druggabilitymentioning

confidence: 99%

Regulator of G Protein Signaling 17 as a Negative Modulator of GPCR Signaling in Multiple Human Cancers

Hayes

Roman

2016

AAPS J

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Abstract. Regulators of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling networks by terminating signals produced by active Gα subunits. RGS17, a member of the RZ subfamily of RGS proteins, is typically only expressed in appreciable amounts in the human central nervous system, but previous works have shown that RGS17 expression is selectively upregulated in a number of malignancies, including lung, breast, prostate, and hepatocellular carcinoma. In addition, this upregulation of RGS17 is associated with a more aggressive cancer phenotype, as increased proliferation, migration, and invasion are observed. Conversely, decreased RGS17 expression diminishes the response of ovarian cancer cells to agents commonly used during chemotherapy. These somewhat contradictory roles of RGS17 in cancer highlight the need for selective, high-affinity inhibitors of RGS17 to use as chemical probes to further the understanding of RGS17 biology. Based on current evidence, these compounds could potentially have clinical utility as novel chemotherapeutics in the treatment of lung, prostate, breast, and liver cancers. Recent advances in screening technologies to identify potential inhibitors coupled with increasing knowledge of the structural requirements of RGS-Gα protein-protein interaction inhibitors make the future of drug discovery efforts targeting RGS17 promising. This review highlights recent findings related to RGS17 as both a canonical and atypical RGS protein, its role in various human disease states, and offers insights on small molecule inhibition of RGS17.

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“…There are some identified small molecule inhibitors of RGS proteins that show promises in subtype selectivity and potency in altering RGS activity, and are being evaluated in vivo [65,66]. Furthermore, there are a few reported small-molecule RGS inhibitors that are capable of altering G protein signaling by disrupting the Gα-RGS interaction through an allosteric modulation [67,68]. The availability of RGS protein inhibitors will not only provide utility for studying the in vivo function of RGS proteins but also provide a potential means for pharmacological intervention of psychostimulant addiction.…”

Section: Rgs Proteins As Potential Targets For Drug Abusementioning

confidence: 99%

Dysregulation of RGS Proteins by Psychostimulants

2014

J Addict & Prev

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Regulator of G protein signaling (RGS) proteins are a class of proteins that negatively modulate GPCR-mediated G protein signaling. The distribution of subtypes of RGS proteins is brain region specific. Several subtypes of RGS proteins are present in the mesolimbic dopaminergic pathway and are subjected to modulation by psychostimulants. Acute or chronic exposure to psychostimulants induces changes in mRNA levels of RGS in a subtype-, brain region-, and time-dependent manner. The dynamic changes in the abundance of RGS proteins by psychostimulant treatment may be associated with dopamine receptor sensitization or desensitization, a potential mechanism underlying drug sensitization or tolerance. Small molecule RGS inhibitors are useful tools for studying in vivo function of RGS proteins and are potential therapeutics for the treatment of psychostimulant addiction.

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Allosteric Inhibition of the Regulator of G Protein Signaling–Gα Protein–Protein Interaction by CCG-4986

Cited by 45 publications

References 34 publications

Reversible, Allosteric Small-Molecule Inhibitors of Regulator of G Protein Signaling Proteins

Reversible, Allosteric Small-Molecule Inhibitors of Regulator of G Protein Signaling Proteins

Regulator of G Protein Signaling 17 as a Negative Modulator of GPCR Signaling in Multiple Human Cancers

Dysregulation of RGS Proteins by Psychostimulants

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