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CCG 50014

RGS4 Inhibitor,potent and selective CAS# 883050-24-6

CCG 50014

Catalog No. BCC4897----Order now to get a substantial discount!

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Chemical structure

CCG 50014

3D structure

Chemical Properties of CCG 50014

Cas No. 883050-24-6 SDF Download SDF
PubChem ID 2733079 Appearance Powder
Formula C16H13FN2O2S M.Wt 316.35
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 100 mM in DMSO
Chemical Name 4-[(4-fluorophenyl)methyl]-2-(4-methylphenyl)-1,2,4-thiadiazolidine-3,5-dione
SMILES CC1=CC=C(C=C1)N2C(=O)N(C(=O)S2)CC3=CC=C(C=C3)F
Standard InChIKey QUIIIYITNGOFEI-UHFFFAOYSA-N
Standard InChI InChI=1S/C16H13FN2O2S/c1-11-2-8-14(9-3-11)19-15(20)18(16(21)22-19)10-12-4-6-13(17)7-5-12/h2-9H,10H2,1H3
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of CCG 50014

DescriptionPotent and selective inhibitor of regulator of G-protein signaling 4 (RGS4) protein (IC50 values are 30.1 nM and 11.0 μM for RGS4 and RGS8 respectively). Exhibits >20-fold selectivity for RGS4 over other RGS proteins.

CCG 50014 Dilution Calculator

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CCG 50014 Molarity Calculator

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Preparing Stock Solutions of CCG 50014

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.1611 mL 15.8053 mL 31.6106 mL 63.2211 mL 79.0264 mL
5 mM 0.6322 mL 3.1611 mL 6.3221 mL 12.6442 mL 15.8053 mL
10 mM 0.3161 mL 1.5805 mL 3.1611 mL 6.3221 mL 7.9026 mL
50 mM 0.0632 mL 0.3161 mL 0.6322 mL 1.2644 mL 1.5805 mL
100 mM 0.0316 mL 0.1581 mL 0.3161 mL 0.6322 mL 0.7903 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on CCG 50014

CCG-50014 is a potent and small molecule RGS inhibitor (IC50= 30 nM for RGS4, more than 20 fold selectivity for RGS4 over other RGS proteins). It is a GTPase activating protein that binds to the Gα –subunits of activated heterotrimeric G-proteins and boost GTP hydrolysis rate. [1][2]

RGS (regulator of G protein signaling) inactivates G proteins by promoting GTPase hydrolysis ability of the alphas subunit, thus inhibits the G protein signaling transduction.

In living HEK293T cells, CCG-50014 inhibited Gαo-dependent membrane translocation of GFP-RGS4. HEK293T cell transfected with GFP-RGS4 and Gαo with vehicle (0.1% DMSO) did not changed the membrane localization of RGS4, CCG-50014 (100 μM) reversed the membrane localization of RGS. [1]

References:
[1] Blazer LL, Zhang H, Casey EM et al.  A nanomolar-potency small molecule inhibitor of regulator of G-protein signaling proteins. Biochemistry. 2011 Apr 19;50(15):3181-92.
[2] Vashisth H, Storaska AJ, Neubig RR et al.  Conformational dynamics of a regulator of G-protein signaling protein reveals a mechanism of allosteric inhibition by a small molecule. ACS Chem Biol. 2013 Dec 20;8(12):2778-84.

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References on CCG 50014

CCG: an integrative resource of cancer protein-coding genes and long noncoding RNAs.[Pubmed:28147217]

Discov Med. 2016 Dec;22(123):351-359.

The identification of cancer genes remains a main aim of cancer research. With the advances of high-throughput sequencing technologies, thousands of novel cancer genes were identified through recurrent mutation analyses and differential expression analyses between normal tissues and tumors in large populations. Many databases were developed to document the cancer genes. However, no public database providing both cancer protein-coding genes and cancer lncRNAs is available presently. Here, we present the Catalogue of Cancer Genes (CCG) database (http://ccg.xingene.net), a catalogue of cancer genes. It includes both well-supported and candidate cancer protein-coding genes and cancer lncRNAs collected from literature search and public databases. In addition, uniform genomic aberration information (such as somatic mutation and copy number variation) and drug-gene interactions were assigned to cancer genes in the database. CCG represents an effort on integrative assembly of well-supported and candidate cancer protein-coding and long noncoding RNA genes and takes advantages of high-throughput sequencing results on large populations. With the help of CCG, users can easily access a comprehensive list of cancer genes as well as genomic aberration related with these genes. The availability of integrative information will facilitate the understanding of cancer mechanisms. In addition, drug-gene information in CCG provides a useful guide to the development of new anti-cancer drugs and selection of rational combination therapies.

Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma.[Pubmed:28285914]

Bioorg Med Chem Lett. 2017 Apr 15;27(8):1744-1749.

We recently reported the development of a novel inhibitor of Rho-mediated gene transcription (1, CCG-203971) that is efficacious in multiple animal models of acute fibrosis, including scleroderma, when given intraperitoneally. The modest in vivo potency and poor pharmacokinetics (PK) of this lead, however, make it unsuitable for long term efficacy studies. We therefore undertook a systematic medicinal chemistry effort to improve both the metabolic stability and the solubility of 1, resulting in the identification of two analogs achieving over 10-fold increases in plasma exposures in mice. We subsequently showed that one of these analogs (8f, CCG-232601) could inhibit the development of bleomycin-induced dermal fibrosis in mice when administered orally at 50mg/kg, an effect that was comparable to what we had observed earlier with 1 at a 4-fold higher IP dose.

Conformational dynamics of a regulator of G-protein signaling protein reveals a mechanism of allosteric inhibition by a small molecule.[Pubmed:24093330]

ACS Chem Biol. 2013 Dec 20;8(12):2778-84.

Regulators of G protein signaling (RGS) proteins are key players in regulating signaling via G protein-coupled receptors. RGS proteins directly bind to the Galpha-subunits of activated heterotrimeric G-proteins, and accelerate the rate of GTP hydrolysis, thereby rapidly deactivating G-proteins. Using atomistic simulations and NMR spectroscopy, we have studied in molecular detail the mechanism of action of CCG-50014, a potent small molecule inhibitor of RGS4 that covalently binds to cysteine residues on RGS4. We apply temperature-accelerated molecular dynamics (TAMD) to carry out enhanced conformational sampling of apo RGS4 structures, and consistently find that the alpha5-alpha6 helix pair of RGS4 can spontaneously span open-like conformations, allowing binding of CCG-50014 to the buried side-chain of Cys95. Both NMR experiments and MD simulations reveal chemical shift perturbations in residues in the vicinity of inhibitor binding site as well as in the RGS4-Galpha binding interface. Consistent with a loss of G-protein binding, GAP activity, and allosteric mechanism of action of CCG-50014, our simulations of the RGS4-Galpha complex in the presence of inhibitor suggest a relatively unstable protein-protein interaction. These results have potential implications for understanding how the conformational dynamics among RGS proteins may play a key role in the sensitivity of inhibitors.

Small Molecule Inhibitors of Regulator of G Protein Signalling (RGS) Proteins.[Pubmed:22368763]

ACS Med Chem Lett. 2012 Feb 9;3(2):146-150.

Recently regulators of G protein signalling (RGS) proteins have emerged as potential therapeutic targets since they provide an alternative method of modulating the activity of GPCRs, the target of so many drugs. Inhibitors of RGS proteins must block a protein-protein interaction (RGS-Galpha), but also be cell and, depending on the therapeutic target, blood brain barrier permeable. A lead compound (1a) was identified as an inhibitor of RGS4 in a screening assay and this has now been optimised for activity, selectivity and solubility. The newly developed ligands (11b, 13) display substantial selectivity over the closely related RGS8 protein, lack the off-target calcium mobilisation activity of the lead 1a and have excellent aqueous solubility. They are currently being evaluated in vivo in rodent models of depression.

A nanomolar-potency small molecule inhibitor of regulator of G-protein signaling proteins.[Pubmed:21329361]

Biochemistry. 2011 Apr 19;50(15):3181-92.

Regulators of G-protein signaling (RGS) proteins are potent negative modulators of signal transduction through G-protein-coupled receptors. They function by binding to activated (GTP-bound) Galpha subunits and accelerating the rate of GTP hydrolysis. Modulation of RGS activity by small molecules is an attractive mechanism for fine-tuning GPCR signaling for therapeutic and research purposes. Here we describe the pharmacologic properties and mechanism of action of CCG-50014, the most potent small molecule RGS inhibitor to date. It has an IC(50) for RGS4 of 30 nM and is >20-fold selective for RGS4 over other RGS proteins. CCG-50014 binds covalently to the RGS, forming an adduct on two cysteine residues located in an allosteric regulatory site. It is not a general cysteine alkylator as it does not inhibit activity of the cysteine protease papain at concentrations >3000-fold higher than those required to inhibit RGS4 function. It is also >1000-fold more potent as an RGS4 inhibitor than are the cysteine alkylators N-ethylmaleimide and iodoacetamide. Analysis of the cysteine reactivity of the compound shows that compound binding to Cys(107) in RGS8 inhibits Galpha binding in a manner that can be reversed by cleavage of the compound-RGS disulfide bond. If the compound reacts with Cys(160) in RGS8, the adduct induces RGS denaturation, and activity cannot be restored by removal of the compound. The high potency and good selectivity of CCG-50014 make it a useful tool for studying the functional roles of RGS4.

Description

CCG-50014 is the most potent against the regulator of G-protein signaling protein type 4 (RGS4) (IC50 =30 nM) and is >20-fold selective for RGS4 over other RGS proteins. CCG-50014 binds covalently to the RGS, forming an adduct on two cysteine residues located in an allosteric regulatory site. CCG50014, reduces nociceptive responses and enhances opioid-mediated analgesic effects in the mouse formalin test.

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