NSC 663284

Cdc25 phosphatase inhibitor; blocks cdk1 and cdk2 activation CAS# 383907-43-5

NSC 663284

Catalog No. BCC7199----Order now to get a substantial discount!

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Chemical structure

NSC 663284

3D structure

Chemical Properties of NSC 663284

Cas No. 383907-43-5 SDF Download SDF
PubChem ID 379077 Appearance Powder
Formula C15H16ClN3O3 M.Wt 321.76
Type of Compound N/A Storage Desiccate at -20°C
Synonyms DA-3003-1
Solubility Soluble to 50 mM in DMSO and to 50 mM in ethanol
Chemical Name 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione
SMILES C1COCCN1CCNC2=C(C(=O)C3=C(C2=O)N=CC=C3)Cl
Standard InChIKey BMKPVDQDJQWBPD-UHFFFAOYSA-N
Standard InChI InChI=1S/C15H16ClN3O3/c16-11-13(18-4-5-19-6-8-22-9-7-19)15(21)12-10(14(11)20)2-1-3-17-12/h1-3,18H,4-9H2
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 NSC 663284

DescriptionPotent, selective inhibitor of Cdc25 dual specificity phosphatases (Ki values are 29, 95 and 89 nM for human Cdc25A, Cdc25B2 and Cdc25C respectively); > 20- and > 450-fold selective over VHR and PTP1B phosphatases respectively. Arrests cells at both G1 and G2/M phase and blocks cdk2 and cdk1 activation. Blocks proliferation of a range of human tumor cell lines (IC50 = 0.2 - 35 μM).

NSC 663284 Dilution Calculator

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NSC 663284 Molarity Calculator

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Preparing Stock Solutions of NSC 663284

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.1079 mL 15.5395 mL 31.0791 mL 62.1581 mL 77.6977 mL
5 mM 0.6216 mL 3.1079 mL 6.2158 mL 12.4316 mL 15.5395 mL
10 mM 0.3108 mL 1.554 mL 3.1079 mL 6.2158 mL 7.7698 mL
50 mM 0.0622 mL 0.3108 mL 0.6216 mL 1.2432 mL 1.554 mL
100 mM 0.0311 mL 0.1554 mL 0.3108 mL 0.6216 mL 0.777 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 NSC 663284

NSC 663284 is a Cdc25 dual specificity phosphatases inhibitor with an IC50 of 0.21 μM.

In Vitro:The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signaling processes and cell proliferation. NSC 663284 exhibits mixed competitive kinetics against Cdc25A, Cdc25B2, and Cdc25C with Ki values of 29, 95, and 89 nM, respectively. NSC 663284 blocks cellular Erk dephosphorylation caused by ectopic Cdc25A expression. NSC 663284 displays a strong preference for Cdc25B2 as compared with VHR or PTP1B, the relative IC50 values for Cdc25B2 are 20- and 450-fold lower than for VHR or PTP1B, respectively. NSC 663284 blocks cell proliferation and the actions of cellular cdc25a. NSC 663284 has a mean IC50 value in the NCI 60 Cell Human Tumor Panel of 1.5 (0.6 µM when cells are treated for 48 h). Most sensitive are human breast cancer MDA-MB-435 and MDA-N cells, which have IC50 values of 0.2 µM[1].

In Vivo:NSC 663284 inhibits the growth of subcutaneous human colon HT29 xenografts in SCID mice. After a single i.v. dose of 5 mg/kg, NSC 663284 is not detectable in plasma or tissues beyond 5 min. Following NSC 663284 treatment of tumor-bearing SCID mice, reduces glutathione concentrations in HT29 tumor are decreased to a greater extent and remained decreased for longer than the reduced glutathione concentrations in liver and kidneys[2].

References:
[1]. Lazo JS, et al. Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25. J Med Chem. 2001 Nov 22;44(24):4042-9. [2]. Guo J, et al. Pharmacology and antitumor activity of a quinolinedione Cdc25 phosphatase inhibitor DA3003-1 (NSC 663284). Anticancer Res. 2007 Sep-Oct;27(5A):3067-73.

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References on NSC 663284

Pharmacology and antitumor activity of a quinolinedione Cdc25 phosphatase inhibitor DA3003-1 (NSC 663284).[Pubmed:17970046]

Anticancer Res. 2007 Sep-Oct;27(5A):3067-73.

Cdc25 protein phosphatases are regulators of cyclin-dependent kinases and are often highly expressed in human malignancies. Few small molecule inhibitors of the Cdc25 phosphatase family have been identified and little is known about their disposition, metabolism or efficacy in xenograft models. In this study, the efficacy, pharmacokinetics, and metabolism of a potent quinolinedione Cdc25 phosphatase inhibitor, DA3003-1, in mice was examined. DA3003-1 inhibited the growth of subcutaneous human colon HT29 xenografts in SCID mice. After a single i.v. dose of 5 mg/kg, DA3003-1 was not detectable in plasma or tissues beyond 5 min. In vitro studies showed that DA3003-1 was rapidly dechlorinated and conjugated to glutathione. Following DA3003-1 treatment of tumor-bearing SCID mice, reduced glutathione concentrations in HT29 tumor were decreased to a greater extent and remained decreased for longer than the reduced glutathione concentrations in liver and kidneys. These studies suggest that the minimal antitumor activity of DA3003-1 in mice may be due to its rapid metabolism.

Redox regulation of Cdc25B by cell-active quinolinediones.[Pubmed:16155209]

Mol Pharmacol. 2005 Dec;68(6):1810-20.

Intracellular reduction and oxidation pathways regulate protein functionality through both reversible and irreversible mechanisms. The Cdc25 phosphatases, which control cell cycle progression, are potential subjects of oxidative regulation. Many of the more potent Cdc25 phosphatase inhibitors reported to date are quinones, which are capable of redox cycling. Therefore, we used the previously characterized quinolinedione Cdc25 inhibitor DA3003-1 [NSC 663284 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] and a newly synthesized congener JUN1111 [7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] to test the hypothesis that quinone inhibitors of Cdc25 regulate phosphatase activity through redox mechanisms. Like DA3003-1, JUN1111 selectively inhibited Cdc25 phosphatases in vitro in an irreversible, time-dependent manner and arrested cells in the G1 and G2/M phases of the cell cycle. It is noteworthy that both DA3003-1 and JUN1111 directly inhibited Cdc25B activity in cells. Depletion of glutathione increased cellular sensitivity to DA3003-1 and JUN1111, and in vitro Cdc25B inhibition by these compounds was sensitive to pH, catalase, and reductants (dithiothreitol and glutathione), consistent with oxidative inactivation. In addition, both DA3003-1 and JUN1111 rapidly generated intracellular reactive oxygen species. Analysis of Cdc25B by mass spectrometry revealed sulfonic acid formation on the catalytic cysteine of Cdc25B after in vitro treatment with DA3003-1. These results indicate that irreversible oxidation of the catalytic cysteine of Cdc25B is indeed a mechanism by which these quinolinediones inactivate this protein phosphatase.

Dual G1 and G2 phase inhibition by a novel, selective Cdc25 inhibitor 6-chloro-7-[corrected](2-morpholin-4-ylethylamino)-quinoline-5,8-dione.[Pubmed:12356752]

J Biol Chem. 2002 Dec 6;277(49):46877-85.

The Cdc25 dual specificity phosphatases coordinate cell cycle progression, but potent and selective inhibitors have generally been unavailable. In the present study, we have examined one potential inhibitor, 6-chloro-7-(2-morpholin-4-ylethylamino)-quinoline-5,8-dione (NSC 663284), that was identified in the compound library of the National Cancer Institute [corrected]. We found that NSC 663284 arrested synchronized cells at both G(1) and G(2)/M phase, and blocked dephosphorylation and activation of Cdk2 and Cdk1 in vivo, as predicted for a Cdc25 inhibitor. Using the natural Cdc25A substrate, Tyr(15)-phosphorylated Cdk2/cyclin A, we demonstrated that NSC 663284 blocked reactivation of Cdk2/cyclin A kinase by Cdc25A catalytic domain in vitro. In-gel trypsin digestion followed by capillary liquid chromatography-electrospray ionization mass spectrometry and tandem mass spectrometry revealed the direct binding of NSC 663284 to one of the two serine residues in the active site loop HCEFSSER of the Cdc25A catalytic domain. Cdc25 binding and inhibition could contribute to the anti-proliferative activity of NSC 663284 and its ability to arrest cell cycle progression. Moreover, NSC 663284 should be a valuable reagent to probe the actions of Cdc25 phosphatases within cells and may also be useful structure for the design of more potent and selective antiproliferative agents.

Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25.[Pubmed:11708908]

J Med Chem. 2001 Nov 22;44(24):4042-9.

The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signaling processes and cell proliferation, but potent and selective inhibitors are lacking. We experimentally examined the 1990 compound National Cancer Institute Diversity Set and then computationally selected from their 140 000 compound repository 30 quinolinediones of which 8 had in vitro mean inhibitory concentrations <1 microM. The most potent was 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione (NSC 663284), which was 20- and 450-fold more selective against Cdc25B(2) as compared with VHR or PTP1B phosphatases, respectively. NSC 663284 exhibited mixed competitive kinetics against Cdc25A, Cdc25B(2), and Cdc25C with K(i) values of 29, 95, and 89 nM, respectively. As compared with NSC 663284, the regioisomer 7-chloro-6-(2-morpholin-4-ylethylamino)quinoline-5,8-dione was 3-fold less active against Cdc25B(2) in vitro and less potent as a growth inhibitor of human breast cancer cells. Computational electrostatic potential mapping suggested the need for an electron-deficient 7-position for maximal inhibitor activity. Using a chemical complementation assay, we found that NSC 663284 blocked cellular Erk dephosphorylation caused by ectopic Cdc25A expression.

Description

NSC 663284 is a potent, cell-permeable, and irreversible Cdc25 dual specificity phosphatase inhibitor, has an IC50 for Cdc25B2 of 0.21 μM. NSC 663284 exhibits mixed competitive kinetics against Cdc25A, Cdc25B(2), and Cdc25C with Ki values of 29, 95, and 89 nM, respectively. NSC 663284 inhibits NSD2 (IC50 of 170 nM) through a direct interaction with the catalytic SET domain (Kd of 370 nM).

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