AS601245

c-Jun NH2-terminal protein kinase inhibitor CAS# 345987-15-7

AS601245

Catalog No. BCC6464----Order now to get a substantial discount!

Product Name & Size Price Stock
AS601245:1mg $48.00 In stock
AS601245:2mg $82.00 In stock
AS601245:5mg $192.00 In stock
AS601245:10mg $336.00 In stock
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Quality Control of AS601245

Quality Control & MSDS

Number of papers citing our products

Chemical structure

AS601245

3D structure

Chemical Properties of AS601245

Cas No. 345987-15-7 SDF Download SDF
PubChem ID 10109823 Appearance Powder
Formula C20H16N6S M.Wt 372.45
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 10 mg/mL (26.85 mM; Need ultrasonic)
Chemical Name 2-(1,3-benzothiazol-2-yl)-2-[2-(2-pyridin-3-ylethylamino)pyrimidin-4-yl]acetonitrile
SMILES C1=CC=C2C(=C1)N=C(S2)C(C#N)C3=NC(=NC=C3)NCCC4=CN=CC=C4
Standard InChIKey RCYPVQCPYKNSTG-UHFFFAOYSA-N
Standard InChI InChI=1S/C20H16N6S/c21-12-15(19-25-17-5-1-2-6-18(17)27-19)16-8-11-24-20(26-16)23-10-7-14-4-3-9-22-13-14/h1-6,8-9,11,13,15H,7,10H2,(H,23,24,26)
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 AS601245

DescriptionAS601245 is a JNK Inhibitor with IC50s of 150, 220, and 70 nM for three JNK human isoforms (hJNK1, hJNK2, and hJNK3), respectively.In Vitro:AS601245 inhibits isolated hJNK3 in an ATP-competitive manner. Selectivity of AS601245 is tested against a large panel of kinases. AS601245 exhibits 10- to 20-fold selectivity over c-src, CDK2, and c-Raf and more than 50- to 100-fold selectivity over a range of Ser/Thr- and Tyr-protein kinases[1]. The effects of AS601245 and Clofibrate alone or in association are analysed on proliferation, apoptosis, differentiation and the gene expression profile of CaCo-2 human colon cancer cells. Reduction of cell proliferation, accompanied by the modulation of p21 expression is observed in HepG2 cells, also. 5 μM Clofibrate, 0.1 μM AS601245, and the combined treatment with the two substances do not cause acute toxicity in HepG2 cells. All treatments reduce cell proliferation starting from 48 hours after the beginning of experiments, and the inhibitory effect reaches the maximum at 72 hours[2].In Vivo:AS601245 is a potent inhibitor of LPS-induced TNF-α release in mice. Administered orally at 0.3, 1, 3, and 10 mg/kg, AS601245 decreases the TNF-α release in a dose-dependent manner. AS601245 (40, 60, and 80 mg/kg) administered i.p. provides significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. This effect is mediated by JNK inhibition and therefore by c-Jun expression and phosphorylation. A significant neuroprotective effect of AS601245 administered either by i.p. injection (6, 18, and 60 mg/kg) or as i.v. bolus (1 mg/kg) followed by an i.v. infusion (0.6 mg/kg/h) is also observed in rats after focal cerebral ischemia[1].

References:
[1]. Carboni S, et al. AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. J Pharmacol Exp Ther. 2004 Jul;310(1):25-32. [2]. Cerbone A, et al. AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon CancerCells. PPAR Res. 2012;2012:269751.

Protocol

Kinase Assay [1]
Rat JNK3 assays are performed in 96-well low binding Corning MTT plates: 0.5 μg of recombinant, preactivated GST-JNK3 is incubated with 1 μg of recombinant, biotinylated GST-c-Jun and 2 μM [33Pγ]ATP (2 nCi/μl), in the presence or absence of compounds according to formula I and in a reaction volume of 50 μL containing 50 mM Tris-HCl, pH 8.0; 10 mM MgCl2, 1 mM Dithiothreitol, and 100 μM NaVO4, for 120 min and at room temperature. The reaction is stopped by the addition of 200 μL of a solution containing 250 μg of Streptavidin-coated SPA beads, 5 mM EDTA, 0.1% Triton X-100, and 50 μM ATP, in phosphate saline buffer and further incubation at room temperature for 60 min. After incubation, beads are sedimented by centrifugation at 1500g for 5 min, resuspended in 200 μL of phosphate-buffered saline (PBS) containing 5 mM EDTA, 0.1% Triton X-100, and 50 μM ATP and the radioactivity is measured in a scintillation beta counter, following further sedimentation of the beads by settling down for 60 min at room temperature. Similar method is used to demonstrate inhibition of JNK1 and JNK2[1].

Cell Assay [2]
CaCo-2 cell proliferation is evaluated by using the kit “CellTiter-Glo Luminescent Cell Viability Assay”. This highly sensitive assay detects the luminescence released by the metabolically active cells. Quantification of luminescence is expressed as RLU (relative light unit). For the proliferation experiments, treatments are performed by adding the drugs (e.g., 0.1 μM AS601245) to the CaCo-2 cells seeded at about 4,000 cells/well in a 96-well plate. HepG2 cell proliferation is analysed through the MTT method. Briefly, 1500 cells/well are seeded in 200 μL of serum-supplemented media and the following day treated with the drugs (e.g, 0.1 μM AS601245). 20 μL of 5 mg/mL thiazolyl blue tetrazolium bromide is subsequently added to the cells and removed 2 hours later. 100 μL of DMSO is added to the cells, and the absorbance is recorded at 570 nm through a 96 well plate ELISA reader. Viability is evaluated through Trypan blue exclusion test[2].

Animal Administration [1]
Mice[1] C3H/HEN mice receive an oral treatment with AS601245 (0.3, 1, 3, or 10 mg/kg). Fifteen minutes later, Endotoxins (0.3 mg/kg) are i.p. injected. Heparinized whole blood is collected by retro orbital puncture under isoflurane anesthesia. TNF-α is determined in plasma using an enzyme-linked immunosorbent assay kit. Control animals receive 0.5% CMC/0.25% Tween 20 (10 mL/kg) as vehicle[1]. Rats[1] Wistar rats are randomly divided into a vehicle-treated control group, a reference compound-treated group, and a drug-treated group. The reference compound-treated group receive MK-801 (3 mg/kg i.p.) administered 1 h postischemia onset. The drug-treated group receive AS601245 (6, 18, or 60 mg/kg) administered at the initiation of reperfusion and 5 h later. Control animals receive 0.9% saline (10 ml/kg i.p.). Wistar rats are randomly divided into three groups. The reference compound-treated group receive MK-801 (3 mg/kg i.p.) administered 1 h postischemia onset. The drug-treated group receive an intravenous bolus of AS601245 (1 mg/kg) injected at the initiation of reperfusion followed by an intravenous infusion with a flow of 0.6 mg/kg/h during 22 h. Control animals receive a bolus plus an intravenous infusion of 0.9% saline (10 mL/kg)[1].

References:
[1]. Carboni S, et al. AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. J Pharmacol Exp Ther. 2004 Jul;310(1):25-32. [2]. Cerbone A, et al. AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon CancerCells. PPAR Res. 2012;2012:269751.

AS601245 Dilution Calculator

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AS601245 Molarity Calculator

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Preparing Stock Solutions of AS601245

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.6849 mL 13.4246 mL 26.8492 mL 53.6985 mL 67.1231 mL
5 mM 0.537 mL 2.6849 mL 5.3698 mL 10.7397 mL 13.4246 mL
10 mM 0.2685 mL 1.3425 mL 2.6849 mL 5.3698 mL 6.7123 mL
50 mM 0.0537 mL 0.2685 mL 0.537 mL 1.074 mL 1.3425 mL
100 mM 0.0268 mL 0.1342 mL 0.2685 mL 0.537 mL 0.6712 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 AS601245

Description:

IC50: 150, 220, and 70 nM for hJNK1, hJNK2, and hJNK3, respectively

Recent evidence suggests activation of the c-Jun NH2-terminal protein kinase (JNK) signal transduction pathway may play a role in ischemia-induced cell death. Therefore, preventing the activation of JNK, or c-Jun phosphorylation could be neuroprotective. AS601245 is a c-Jun NH2-terminal protein kinase inhibitor.

In vitro: AS601245 demonstrated a nonspecific inhibition of the three JNK human isoforms. AS601245 inhibits isolated hJNK3 in an ATPcompetitive manner. Selectivity of AS601245 was tested against a large panel of kinases. It exhibited 10- to 20-fold selectivity over c-src, CDK2, and c-Raf and more than 50- to 100-fold selectivity over a range of Tyr- and Ser/Thr-protein kinases [1].

In vivo: AS601245 administered i.p. provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. This effect is mediated by JNK inhibition and thus by c-Jun expression and phosphorylation. A significant neuroprotective effect of AS601245 administered either by i.p. injection or as i.v. bolus followed by an i.v. infusion was also observed in rats after focal cerebral ischemia [1].

Clinical trial: Up to now, AS601245 is still in the preclinical development stage.

Reference:
[1] Carboni S, Hiver A, Szyndralewiez C, Gaillard P, Gotteland JP, Vitte PA.  AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. J Pharmacol Exp Ther. 2004 Jul;310(1):25-32. Epub 2004 Feb 26.

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References on AS601245

AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon Cancer Cells.[Pubmed:22619672]

PPAR Res. 2012;2012:269751.

PPARalphas are nuclear receptors highly expressed in colon cells. They can be activated by the fibrates (clofibrate, ciprofibrate etc.) used to treat hyperlipidemia. Since PPARalpha transcriptional activity can be negatively regulated by JNK, the inhibition of JNK activity could increase the effectiveness of PPARalpha ligands. We analysed the effects of AS601245 (a JNK inhibitor) and clofibrate alone or in association, on proliferation, apoptosis, differentiation and the gene expression profile of CaCo-2 human colon cancer cells. Proliferation was inhibited in a dose-dependent way by clofibrate and AS601245. Combined treatment synergistically reduced cell proliferation, cyclin D1 and PCNA expression and induced apoptosis and differentiation. Reduction of cell proliferation, accompanied by the modulation of p21 expression was observed in HepG2 cells, also. Gene expression analysis revealed that some genes were highly modulated by the combined treatment and 28 genes containing PPRE were up-regulated, while clofibrate alone was ineffective. Moreover, STAT3 signalling was strongly reduced by combined treatment. After combined treatment, the binding of PPARalpha to PPRE increased and paralleled with the expression of the PPAR coactivator MED1. Results demonstrate that combined treatment increases the effectiveness of both compounds and suggest a positive interaction between PPARalpha ligands and anti-inflammatory agents in humans.

Rosiglitazone and AS601245 decrease cell adhesion and migration through modulation of specific gene expression in human colon cancer cells.[Pubmed:22761953]

PLoS One. 2012;7(6):e40149.

PPARs are nuclear receptors activated by ligands. Activation of PPARgamma leads to a reduction of adhesion and motility in some cancer models. PPARgamma transcriptional activity can be negatively regulated by JNK-mediated phosphorylation. We postulated that the use of agents able to inhibit JNK activity could increase the effectiveness of PPARgamma ligands. We analysed the effects of rosiglitazone (PPARgamma ligand) and AS601245 (a selective JNK inhibitor) alone or in association on adhesion and migration of CaCo-2, HT29, and SW480 human colon cancer cells and investigated, through microarray analysis, the genes involved in these processes. Cell adhesion and migration was strongly inhibited by rosiglitazone and AS601245. Combined treatment with the two compounds resulted in a greater reduction of the adhesion and migration capacity. Affymetrix analysis in CaCo-2 cells revealed that some genes which were highly modulated by the combined treatment could be involved in these biological responses. Rosiglitazone, AS601245 and combined treatment down-regulated the expression of fibrinogen chains in all three cell lines. Moreover, rosiglitazone, alone or in association with AS601245, caused a decrease in the fibrinogen release. ARHGEF7/beta-PIX gene was highly down-regulated by combined treatment, and western blot analysis revealed that beta-PIX protein is down-modulated in CaCo-2, HT29 and SW480 cells, also. Transfection of cells with beta-PIX gene completely abrogated the inhibitory effect on cell migration, determined by rosiglitazone, AS601245 and combined treatment. Results demonstrated that beta-PIX protein is involved in the inhibition of cell migration and sustaining the positive interaction between PPARgamma ligands and anti-inflammatory agents in humans.

AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties.[Pubmed:14988419]

J Pharmacol Exp Ther. 2004 Jul;310(1):25-32.

Recent evidence suggests that activation of the c-Jun NH2-terminal protein kinase (JNK) signal transduction pathway may play a role in ischemia-induced cell death. Thus, preventing the activation of JNK, or c-Jun phosphorylation could be neuroprotective. In the current study, we report that a small molecule, AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile), which has been shown to inhibit the JNK signaling pathway, promotes cell survival after cerebral ischemia. In vivo, AS601245 (40, 60, and 80 mg/kg) administered i.p. provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. This effect is mediated by JNK inhibition and therefore by c-Jun expression and phosphorylation. A significant neuroprotective effect of AS601245 administered either by i.p. injection (6, 18, and 60 mg/kg) or as i.v. bolus (1 mg/kg) followed by an i.v. infusion (0.6 mg/kg/h) was also observed in rats after focal cerebral ischemia. These data suggest that the use of JNK inhibitors such as AS601245 may be a relevant strategy in the therapy of ischemic insults.

AS601245, a c-Jun NH2-terminal kinase (JNK) inhibitor, reduces axon/dendrite damage and cognitive deficits after global cerebral ischaemia in gerbils.[Pubmed:18026128]

Br J Pharmacol. 2008 Jan;153(1):157-63.

BACKGROUND AND PURPOSE: Based on their proven ability, in animal models of stroke, to reduce damage to brain grey matter, many drugs have been tested in clinical trials but without success. Failure to save axons from injury and to protect functional outcome has been proposed as the major reason for this lack of success. We have previously demonstrated in two rodent models of cerebral ischaemia, that AS601245 (1,3-benzothiazol-2-yl (2-([2-(3-pyridinyl) ethyl] amino)-4 pyrimidinyl) acetonitrile), an inhibitor of the c-Jun NH(2)-terminal kinase (JNK), has neuroprotective properties. The aim of the present study was to further investigate if AS601245 in addition to its ability to protect neurons also could protect neurites and preserve memory after cerebral ischaemia, in gerbils. EXPERIMENTAL APPROACH: Using immunohistochemical techniques and a behavioural test, we studied the effect of the compound AS601245 on neurodegeneration and cognitive deficits after global cerebral ischaemia in gerbils. KEY RESULTS: At a dose of 80 mg kg(-1), i.p., AS601245 reduced damage to neurites by 67% (P<0.001 versus controls) and activation of astrocytes by 84% (P<0.001 versus controls). In addition, AS601245 (80 mg kg(-1), i.p.) prevented ischaemia-induced impairment of memory in the inhibitory avoidance task model. CONCLUSIONS AND IMPLICATIONS: The present results suggest that AS601245 reduced damage to neurites and decreased astrogliosis following global ischaemia and also improved long-term memory, supporting JNK inhibition as a promising therapeutic strategy for ischaemic insults to the CNS.

Description

AS601245 is a cell-permeable JNK Inhibitor with IC50s of 150, 220, and 70 nM for three JNK human isoforms (hJNK1, hJNK2, and hJNK3), respectively.

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