CC0651

E2 enzyme inhibitor CAS# 1319207-44-7

CC0651

Catalog No. BCC4200----Order now to get a substantial discount!

Product Name & Size Price Stock
CC0651:1mg $534.00 In stock
CC0651:2mg $908.00 In stock
CC0651:5mg $2136.00 In stock
CC0651:10mg $3738.00 In stock
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Quality Control of CC0651

Quality Control & MSDS

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Chemical structure

CC0651

3D structure

Chemical Properties of CC0651

Cas No. 1319207-44-7 SDF Download SDF
PubChem ID 53239927 Appearance Powder
Formula C20H21Cl2NO6 M.Wt 442.29
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 56 mg/mL (126.61 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name (2R,3S,4S)-5-[4-(3,5-dichlorophenyl)phenyl]-2,3-dihydroxy-4-[(2-methoxyacetyl)amino]pentanoic acid
SMILES COCC(=O)NC(CC1=CC=C(C=C1)C2=CC(=CC(=C2)Cl)Cl)C(C(C(=O)O)O)O
Standard InChIKey NTCBTNCWNRCBGX-YTQUADARSA-N
Standard InChI InChI=1S/C20H21Cl2NO6/c1-29-10-17(24)23-16(18(25)19(26)20(27)28)6-11-2-4-12(5-3-11)13-7-14(21)9-15(22)8-13/h2-5,7-9,16,18-19,25-26H,6,10H2,1H3,(H,23,24)(H,27,28)/t16-,18-,19+/m0/s1
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 CC0651

DescriptionAllosteric inhibitor of human Cdc34. Inhibits hCdc34-mediated ubiquitination of p27Kip1 (IC50 = 1.72 μM). Exhibits selectivity for hCdc34 over Uba1, Ube2G1, UbcH7, UbcH5, Ube2N (Ubc13), Ube2R2, SMURF2, SspH1 and Rnf168.

Protocol

Kinase Assay [1]
For small-molecule screens, p27Kip1 is ubiquitinated in a 15 μL reaction with 40 nM phospho-p27, 40 nM E1, 5 μM E2, 25 nM SCFSkp2, 25 nM Cks1, and 27.8 μM biotinylated ubiquitin in 40 mM Tris-HCl [pH 7.5], 5 mM MgCl2, 1 mM DTT, and 0.5 mM ATP at 23°C for 3 hr. The reaction is terminated with assay diluent, transferred to 384-well protein A plates coated with 62 ng SC528 antibody, incubated for 1 hr, and washed six times with 10 mM Tris-HCl [pH 7.6], 0.05% Tween20 prior to addition of 25 μL of 0.4 mg/mL europium streptavidin in HEPES [pH 7.6], 1% BSA, 0.2% Tween20 per well. Plates are incubated for 1 hr, washed, and read for Eu-time-resolved fluorescence after addition of 25 μL enhancement solution. For gel-based ubiquitination assays, CC0651 and its analogs are preincubated at the indicated concentrations with 0.5 μg E1, 1-4 μg hCdc34, and 50 ng SCFCdc4, 100 ng SCFFbw7, 150 ng SCFβTrCP, or 50 ng SCFSkp2 for 10-45 min at 4°C in 20 μL reaction buffer (50 mM HEPES [pH 7.5], 10 mM MgCl2, 2 mM ATP, and 50μM DTT). Reactions are initiated by addition of 1μg ubiquitin and respective SCF substrates (50 ng HisSic1 phosphorylated by Cln2-Cdc28, 50ng cyclin E phosphorylated by Cdk2, 25 ng biotinylated IκBα phosphopeptide [KKERLLDDHDpSGLDpSMKDEE], or 50 ng p27Kip1 phosphorylated by cyclin E-Cdk2), incubated at 30°C for 1-3 hr, and products visualized by immunoblot[1].

Cell Assay [1]
PC-3 and HCT116 cell lines are grown in DMEM supplemented with Penicillin/Streptomycin, 2 mM glutamine, and 10% fetal bovine serum (FBS). Lentiviral shRNA constructs for human CDC34, UBE2R2, and nontarget control are used. For proliferation assays, PC-3 cultures are seeded at 5000 cells/well in quadruplicate in 24-well plates, grown for 24 hr, and then infected with lentiviral supernatant. For small-molecule inhibition, cells are seeded in quadruplicate at 500 cells/well in 96-well plates, grown for 24 hr, and treated with compound. Proliferation is measured by MTT assay. PC-3 or HCT 116 cultures are synchronized in G0/G1 by serum starvation for 30 hr and then released by addition of 10% serum. For epistasis experiments, PC-3 cells are infected with CDC34 shRNA for 24 hr, followed by addition of inhibitor and assessment of proliferation after 4 days. Anti-Cdc34, anti-p27, anti-α-tubulin, anti-ubiquitin, and anti-cyclin E antibodies are used[1].

References:
[1]. Ceccarelli DF, et al. An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. Cell. 2011 Jun 24;145(7):1075-87. [2]. Huang H, et al. E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin. Nat Chem Biol. 2014 Feb;10(2):156-63.

CC0651 Dilution Calculator

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Preparing Stock Solutions of CC0651

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.261 mL 11.3048 mL 22.6096 mL 45.2192 mL 56.524 mL
5 mM 0.4522 mL 2.261 mL 4.5219 mL 9.0438 mL 11.3048 mL
10 mM 0.2261 mL 1.1305 mL 2.261 mL 4.5219 mL 5.6524 mL
50 mM 0.0452 mL 0.2261 mL 0.4522 mL 0.9044 mL 1.1305 mL
100 mM 0.0226 mL 0.113 mL 0.2261 mL 0.4522 mL 0.5652 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 CC0651

CC0651 is an allosteric inhibitor of Cdc34 ubiquitin-conjugating enzyme [1].

Ubiquitin-conjugating enzymes (E2 enzymes) are ubiquitin-carrier enzymes and perform the second step in the ubiquitin-proteasome system (UPS) that mediate the conjugation of ubiquitin to proteins for degradation. The E2 enzyme hCdc34 catalyzes the ubiquitination of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes [1].

CC0651 was an allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme and inhibited the ubiquitination of p27Kip1 with IC50 value of 1.72 μM. In human cancer cell lines PC-3, CC0651 inhibited cell proliferation with IC50 value of 20 μM and increased the level of p27Kip1. Also, CC0651 caused production of the hCdc34-ubiquitin conjugate [1]. CC0651 trapped a weak interaction between the E2 donor ubiquitin binding site and ubiquitin. CC0651-Cdc34A-ubiquitin complex reveals that CC0651 engaged a binding pocket formed from ubiquitin and Cdc34A. Also, CC0651 suppressed the spontaneous hydrolysis rate of the ubiquitin thioester-Cdc34A [2].

References:
[1].  Ceccarelli DF, Tang X, Pelletier B, et al. An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. Cell, 2011, 145(7): 1075-1087.
[2].  Huang H, Ceccarelli DF, Orlicky S, et al. E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin. Nat Chem Biol, 2014, 10(2): 156-163.

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References on CC0651

An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme.[Pubmed:21683433]

Cell. 2011 Jun 24;145(7):1075-87.

In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCF(Skp2) substrate p27(Kip1). CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS.

E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin.[Pubmed:24316736]

Nat Chem Biol. 2014 Feb;10(2):156-163.

Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small-molecule inhibitor of the E2 ubiquitin-conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin-binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester without decreasing the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities.

Description

CC0651 is an allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. CC0651 potently (IC50=1.72 μM) inhibits the ubiquitination of p27Kip1, as confirmed by dose-response analysis.

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