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

Blazer, Levi L.; Roman, David L.; Chung, Alfred; Larsen, Martha J.; Greedy, Benjamin; Husbands, Stephen M.; Neubig, Richard R.

doi:10.1124/mol.110.065128

Cited by 77 publications

(87 citation statements)

References 56 publications

(85 reference statements)

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“…Therefore, RGS4 has been increasingly recognized as a promising therapeutic target for inhibition, and specific drug development is currently under way (Blazer et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.Oncogene advance online publication, Word Count:5,868 words Condensed title:Radiation-enhanced mTOR inhibition in glioblastomaWeiler et al. 2 AbstractA relevant mode of resistance to antiangiogenic and radiotherapy appears to be promotion of tumour cell motility and invasiveness in various cancer types, a process commonly referred to as 'evasive resistance' that may underlie progressive disease and complicates further treatment. Hence, a logical advancement in current oncology consists in optimizing antiangiogenic regimens by identifying suitable complementary strategies, ideally targeting cell motility. Here we report that clinically relevant radiation-enhanced inhibition of the mTOR complexes 1 and 2 exercises such a dual control of angiogenesis and invasiveness independent from PTEN/AKT activation in glioblastoma, a tumour entity that is paradigmatic for both excessive vascular proliferation and cell invasion. This is due to a concerted disrupture of the VEGF/VEGFR-2 signalling axis and likewise suppression of RGS4, which we identified to be a key driver of glioblastoma invasiveness. This combined antiangiogenic/antiinvasive approach might be a promising therapeutic option and warrants further clinical investigation in upfront glioblastoma therapy.Weiler et al.3

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“…Therefore, RGS4 has been increasingly recognized as a promising therapeutic target for inhibition, and specific drug development is currently under way (Blazer et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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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%

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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“…RGS then dissociates from Gα-GDP, which is sequestered by βγ, reforming the heterotrimer and priming the cycle for reactivation upon future GPCR-ligand binding events. Adopted from PDB Structures: 1AGR (Gα, RGS), 3SN6 (GPCR, Gα, βγ) (11,73) The most well-established noncanonical function of RGS17 is its ability to act as a scaffold in a complex surrounding the μOR. RGS17, as well as RGS19 and 20, interacts with histidine triad nucleotide binding protein 1(HINT1) through its pCys string, as first identified via Y2H screening for proteins that directly bind to RGS20 (25).…”

Section: Noncanonical Functions and Interactionsmentioning

confidence: 99%

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

Cited by 77 publications

References 56 publications

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

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

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