BIX 02565

RSK2 inhibitor CAS# 1311367-27-7

BIX 02565

Catalog No. BCC4303----Order now to get a substantial discount!

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Quality Control of BIX 02565

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Chemical structure

BIX 02565

3D structure

Chemical Properties of BIX 02565

Cas No. 1311367-27-7 SDF Download SDF
PubChem ID 53246941 Appearance Powder
Formula C26H30N6O2 M.Wt 458.56
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 20.75 mg/mL (45.25 mM; Need ultrasonic and warming)
Chemical Name (5R)-N-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide
SMILES CC1CCNC(=O)C2=CC3=C(N12)C=C(C=C3)C(=O)NC4=NC5=CC=CC=C5N4CCCN(C)C
Standard InChIKey ZHMXXVNQAFCXKK-QGZVFWFLSA-N
Standard InChI InChI=1S/C26H30N6O2/c1-17-11-12-27-25(34)23-15-18-9-10-19(16-22(18)32(17)23)24(33)29-26-28-20-7-4-5-8-21(20)31(26)14-6-13-30(2)3/h4-5,7-10,15-17H,6,11-14H2,1-3H3,(H,27,34)(H,28,29,33)/t17-/m1/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 BIX 02565

DescriptionBIX 02565 is a potent ribosomal S6 kinase 2 (RSK2) inhibitor with IC50 of 1.1 nM.In Vitro:BIX 02565, a potent RSK2 inhibitor (IC50=1.1 nM) targets for the treatment of heart failure secondary to myocardial infarction through indirect NHE inhibition[1]. BIX 02565, a second Rsk inhibitor, protects enzyme active sites from reaction with biotinylated nucleotide acyl phosphates[2].In Vivo:In telemetry-instrumented rats, BIX 02565 (30, 100, and 300 mg/kg p.o. QD for 4 days) elicits concentration-dependent decreases in MAP after each dose (to -39±4 mm Hg on day 4 at Tmax). BIX 02565 produces concentration-dependent relaxation ex vivo in the phenylephrine-constricted rat aortic ring at concentrations above 0.03 μM with a calculated EC50 of 3.1 μM. Subsequently, BIX 02565 is infused in the anesthetized rat in a low-dose (0.1, 0.3, and 1.0 mg/kg per 20 min) and high-dose (1.0, 3.0, and 10.0 mg/kg per 20 min) series of continuous infusions to test the effect of compound on hemodynamics in vivo[1].

References:
[1]. Fryer RM, et al. Mitigation of off-target adrenergic binding and effects on cardiovascular function in the discovery of novel ribosomal S6 kinase 2 inhibitors. Journal of Pharmacology and Experimental Therapeutics (2012), 340(3), 492-500. [2]. Edgar AJ, et al. A combination of SILAC and nucleotide acyl phosphate labelling reveals unexpected targets of the Rsk inhibitor BI-D1870. Biosci Rep. 2013 Dec 17.

Protocol

Kinase Assay [1]
Radioligand binding studies are performed at MDS Pharma Services. Mean percentage inhibition of specific binding or activity is shown for each assay tested, and in selected assays (for BIX 02565) when inhibition of adrenergic binding generally exceeded 50%, an IC50 is determined by a nonlinear least-squares regression analysis. In brief, human RSK2 protein is used to measure kinase activity utilizing Kinase GloPlus that uses a luciferin-luciferase based detection reagent to quantify residual ATP. The relative light unit signal is measured on an LJL Analyst in luminescence mode using 384 aperture; relative light unit signals are converted to percentage of control; the IC50 is fitted to a standard four-parameter logistic equation[1].

Animal Administration [1]
Rats[1] Mean arterial pressure is assessed in conscious, freely moving male Sprague-Dawley rats (n=6/group) instrumented with telemetry transmitters. BIX 02565 (30, 100, and 300 mg/kg p.o. QD) is administered as a solution (10 mL/kg) in a 20% hydroxy-propyl-β-cyclodextran vehicle. Mean arterial pressure is reported from 2 h before (baseline) and 90 h after the first dose; compound is administered at 0, 24, 48, and 72 h. A blood sample is collected from satellite rats (n=3/group) at 1-h after dose (Tmax) on days 1 and 4 for analysis of plasma drug concentrations by mass spectrometry.

References:
[1]. Fryer RM, et al. Mitigation of off-target adrenergic binding and effects on cardiovascular function in the discovery of novel ribosomal S6 kinase 2 inhibitors. Journal of Pharmacology and Experimental Therapeutics (2012), 340(3), 492-500. [2]. Edgar AJ, et al. A combination of SILAC and nucleotide acyl phosphate labelling reveals unexpected targets of the Rsk inhibitor BI-D1870. Biosci Rep. 2013 Dec 17.

BIX 02565 Dilution Calculator

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BIX 02565 Molarity Calculator

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Preparing Stock Solutions of BIX 02565

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.1807 mL 10.9037 mL 21.8074 mL 43.6148 mL 54.5185 mL
5 mM 0.4361 mL 2.1807 mL 4.3615 mL 8.723 mL 10.9037 mL
10 mM 0.2181 mL 1.0904 mL 2.1807 mL 4.3615 mL 5.4518 mL
50 mM 0.0436 mL 0.2181 mL 0.4361 mL 0.8723 mL 1.0904 mL
100 mM 0.0218 mL 0.109 mL 0.2181 mL 0.4361 mL 0.5452 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 BIX 02565

BIX 02565 is a novel inhibitor of ribosomal S6 kinase 2 with IC50 value of 1 nM [1].

Ribosomal S6 kinase (RSK) is a Na/H exchanger (NHE) -activating factor and is important for pH maintenance during the early phase of cellular stress. While, NHE activation leads to Ca2+ overload and cardiac hypertrophy over longer periods [2].

BIX 02565 is a novel RSK2 inhibitor. Also, BIX 02565 inhibited adrenergic ɑ1A-, ɑ1B-, ɑ1D-, ɑ2A-, β2- and imidazoline I2 receptors with IC50 values ranging from 0.052 to 1.820 μM. These receptors played important roles in the regulation of vascular tone and cardiac function [2]. Also, BIX 02565 inhibited LRRK2 and PRKD1 with IC50 values of 16 and 35 nM [1].

In the rat CV screen, BIX 02565 (1, 3 and 10 mg/kg) significantly decreased heart rate (-93 +13 beats/min) and mean arterial pressure (MAP: to -65 +6 mm Hg below baseline). In telemetry-instrumented rats, BIX 02565 (30, 100 and 300 mg/kg for 4 days) reduced MAP (to -39 + 4 mm Hg) in a concentration-dependent way [2].

References:
[1].  Kirrane TM, Boyer SJ, Burke J, et al. Indole RSK inhibitors. Part 2: optimization of cell potency and kinase selectivity. Bioorg Med Chem Lett, 2012, 22(1): 738-742.
[2].  Fryer RM, Muthukumarana A, Chen RR, et al. Mitigation of off-target adrenergic binding and effects on cardiovascular function in the discovery of novel ribosomal S6 kinase 2 inhibitors. J Pharmacol Exp Ther, 2012, 340(3): 492-500.

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References on BIX 02565

TSA and BIX-01294 Induced Normal DNA and Histone Methylation and Increased Protein Expression in Porcine Somatic Cell Nuclear Transfer Embryos.[Pubmed:28114389]

PLoS One. 2017 Jan 23;12(1):e0169092.

The poor efficiency of animal cloning is mainly attributed to the defects in epigenetic reprogramming of donor cells' chromatins during early embryonic development. Previous studies indicated that inhibition of histone deacetylases or methyltransferase, such as G9A, using Trichostatin A (TSA) or BIX-01294 significantly enhanced the developmental efficiency of porcine somatic cell nuclear transfer (SCNT) embryos. However, potential mechanisms underlying the improved early developmental competence of SCNT embryos exposed to TSA and BIX-01294 are largely unclear. Here we found that 50 nM TSA or 1.0 muM BIX-01294 treatment alone for 24 h significantly elevated the blastocyst rate (P < 0.05), while further improvement was not observed under combined treatment condition. Furthermore, co-treatment or TSA treatment alone significantly reduced H3K9me2 level at the 4-cell stage, which is comparable with that in in vivo and in vitro fertilized counterparts. However, only co-treatment significantly decreased the levels of 5mC and H3K9me2 in trophectoderm lineage and subsequently increased the expression of OCT4 and CDX2 associated with ICM and TE lineage differentiation. Altogether, these results demonstrate that co-treatment of TSA and BIX-01294 enhances the early developmental competence of porcine SCNT embryos via improvements in epigenetic status and protein expression.

Beneficial effects of diazepin-quinazolin-amine derivative (BIX-01294) on preimplantation development and molecular characteristics of cloned mouse embryos.[Pubmed:27477633]

Reprod Fertil Dev. 2017 Jun;29(6):1260-1269.

Somatic cell nuclear transfer is frequently associated with abnormal epigenetic modifications that may lead to the developmental failure of cloned embryos. BIX-01294 (a diazepine-quinazoline-amine derivative) is a specific inhibitor of the histone methyltransferase G9a. The aim of the present study was to investigate the effects of BIX-01294 on development, dimethylation of histone H3 at lysine 9 (H3K9), DNA methylation and the expression of imprinted genes in cloned mouse preimplantation embryos. There were no significant differences in blastocyst rates of cloned embryos treated with or without 0.1muM BIX-01294. Relative to clone embryos treated without 0.1muM BIX-01294, exposure of embryos to BIX-01294 decreased histone H3K9 dimethylation and DNA methylation in cloned embryos to levels that were similar to those of in vivo-fertilised embryos at the 2-cell and blastocyst stages. Cloned embryos had lower expression of octamer-binding transcription factor 4 (Oct4) and small nuclear ribonucleoprotein N (Snrpn), but higher expression of imprinted maternally expressed transcript (non-protein coding) (H19) and growth factor receptor-bound protein 10 (Grb10) compared with in vivo-fertilised counterparts. The addition of 0.1muM BIX-01294 to the activation and culture medium resulted in lower H19 expression and higher cyclin dependent kinase inhibitor 1C (Cdkn1c) and delta-like 1 homolog (Dlk1) expression, but had no effect on the expression of Oct4, Snrpn and Grb10. The loss of methylation at the Grb10 cytosine-phosphorous-guanine (CpG) islands in cloned embryos was partially corrected by BIX-01294. These results indicate that BIX-01294 treatment of cloned embryos has beneficial effects in terms of correcting abnormal epigenetic modifications, but not on preimplantation development.

Effect of BIX-01294 on H3K9me2 levels and the imprinted gene Snrpn in mouse embryonic fibroblast cells.[Pubmed:26285804]

Biosci Rep. 2015 Aug 18;35(5). pii: BSR20150064.

Histone H3 lysine 9 dimethylation (H3K9me2) hypermethylation is thought to be a major influential factor in cellular reprogramming, such as somatic cell nuclear transfer (SCNT) and induction of pluripotent stem cells (iPSCs). The diazepin-quinazolin-amine derivative (BIX-01294) specifically inhibits the activity of histone methyltransferase EHMT2 (euchromatic histone-lysine N-methyltransferase 2) and reduces H3K9me2 levels in cells. The imprinted gene small nuclear ribonucleoprotein N (Snrpn) is of particular interest because of its important biological functions. The objective of the present study was to investigate the effect of BIX-01294 on H3K9me2 levels and changes in Snrpn DNA methylation and histone H3K9me2 in mouse embryonic fibroblasts (MEFs). Results showed that 1.3 muM BIX-01294 markedly reduced global levels of H3K9me2 with almost no cellular toxicity. There was a significant decrease in H3K9me2 in promoter regions of the Snrpn gene after BIX-01294 treatment. A significant increase in methylation of the Snrpn differentially methylated region 1 (DMR1) and slightly decreased transcript levels of Snrpn were found in BIX-01294-treated MEFs. These results suggest that BIX-01294 may reduce global levels of H3K9me2 and affect epigenetic modifications of Snrpn in MEFs.

BIX-01294 increases pig cloning efficiency by improving epigenetic reprogramming of somatic cell nuclei.[Pubmed:26604326]

Reproduction. 2016 Jan;151(1):39-49.

Accumulating evidence suggests that faulty epigenetic reprogramming leads to the abnormal development of cloned embryos and results in the low success rates observed in all mammals produced through somatic cell nuclear transfer (SCNT). The aberrant methylation status of H3K9me and H3K9me2 has been reported in cloned mouse embryos. To explore the role of H3K9me2 and H3K9me in the porcine somatic cell nuclear reprogramming, BIX-01294, known as a specific inhibitor of G9A (histone-lysine methyltransferase of H3K9), was used to treat the nuclear-transferred (NT) oocytes for 14-16 h after activation. The results showed that the developmental competence of porcine SCNT embryos was significantly enhanced both in vitro (blastocyst rate 16.4% vs 23.2%, P<0.05) and in vivo (cloning rate 1.59% vs 2.96%) after 50 nm BIX-01294 treatment. BIX-01294 treatment significantly decreased the levels of H3K9me2 and H3K9me at the 2- and 4-cell stages, which are associated with embryo genetic activation, and increased the transcriptional expression of the pluripotency genes SOX2, NANOG and OCT4 in cloned blastocysts. Furthermore, the histone acetylation levels of H3K9, H4K8 and H4K12 in cloned embryos were decreased after BIX-01294 treatment. However, co-treatment of activated NT oocytes with BIX-01294 and Scriptaid rescued donor nuclear chromatin from decreased histone acetylation of H4K8 that resulted from exposure to BIX-01294 only and consequently improved the preimplantation development of SCNT embryos (blastocyst formation rates of 23.7% vs 21.5%). These results indicated that treatment with BIX-01294 enhanced the developmental competence of porcine SCNT embryos through improvements in epigenetic reprogramming and gene expression.

Description

BIX 02565 is a potent ribosomal S6 kinase 2 (RSK2) inhibitor with IC50 of 1.1 nM.

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