NVP-BHG712

EphB4 inhibitor,potent and selective CAS# 940310-85-0

NVP-BHG712

Catalog No. BCC3963----Order now to get a substantial discount!

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Chemical structure

NVP-BHG712

3D structure

Chemical Properties of NVP-BHG712

Cas No. 940310-85-0 SDF Download SDF
PubChem ID 16747388 Appearance Powder
Formula C26H20F3N7O M.Wt 503.48
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 31.25 mg/mL (62.07 mM; Need ultrasonic)
Chemical Name 4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide
SMILES CC1=C(C=C(C=C1)C(=O)NC2=CC=CC(=C2)C(F)(F)F)NC3=NC(=NC4=C3C=NN4C)C5=CN=CC=C5
Standard InChIKey ZCCPLJOKGAACRT-UHFFFAOYSA-N
Standard InChI InChI=1S/C26H20F3N7O/c1-15-8-9-16(25(37)32-19-7-3-6-18(12-19)26(27,28)29)11-21(15)33-23-20-14-31-36(2)24(20)35-22(34-23)17-5-4-10-30-13-17/h3-14H,1-2H3,(H,32,37)(H,33,34,35)
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 NVP-BHG712

DescriptionSelective inhibitor of EphB4 kinase; exhibits selectivity for EphB4 over more than 40 other kinases in vitro, including FGFR3. Inhibits EphB4 autophosphorylation in transiently transfected HEK 293 cells. Also inhibits VEGF-induced angiogenesis in vivo; thought to inhibit EphB4 forward signaling. Orally active.

NVP-BHG712 Dilution Calculator

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Preparing Stock Solutions of NVP-BHG712

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9862 mL 9.9309 mL 19.8618 mL 39.7235 mL 49.6544 mL
5 mM 0.3972 mL 1.9862 mL 3.9724 mL 7.9447 mL 9.9309 mL
10 mM 0.1986 mL 0.9931 mL 1.9862 mL 3.9724 mL 4.9654 mL
50 mM 0.0397 mL 0.1986 mL 0.3972 mL 0.7945 mL 0.9931 mL
100 mM 0.0199 mL 0.0993 mL 0.1986 mL 0.3972 mL 0.4965 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 NVP-BHG712

NVP-BHG712 is a potent inhibitor of EphB4 and VEGFR2 with ED50 value of 25 nM and 4200 nM, respectively [1].

Ephrin type-B receptor 4 (EphB4) is a protein and plays an important role in mediating a variety of developmental processes by working with its ligand. It has been revealed that the over-expression of EphB4 is correlated with several types of tumor [1, 3].

NVP-BHG712 is a potent EphB4 inhibitor and has less inhibition activity on EphB2, EphA2, EphB3 and EphA3. When tested with Hek293 cells transfected different EphRs, administration of NVP-BHG712 inhibited EphRs autophosphorylation in a dose-dependent manner with preference for EphB4, followed by EphB2, EphA2, EphB3 and EphA3 [1]. In HEK293/ABCC 10 cell line, NVP-BHG712 treatment markedly increased cells sensitivity to paclitaxel at the dose of 0.25 μM and 0.5μM [2]. When treated synovial sarcoma cell line with NVP-BHG712, the result showed that it markedly decreased cell proliferation rate and vitality [3].

In VEGF driven angiogenesis tissue model, NVP-BHG712 treatment significantly inhibited VEGF stimulated tissue formation and vascularization by functioning on EphB4 which involved in VEGF driven angiogenesis [1]. In HEK293/ABCC 10 cells subcutaneous xenograft mouse model, co-administration of NVP-BHG712 (25 mg/kg) and paclitaxel (15 mg/kg) markedly decreased tumor volumes, sizes and weights [2]. Using an appropriate sarcoma lung metastasis xenograft model, NVP-BHG712 decreased lung metastasis formation (p?

References:
[1].  Martiny-Baron, G., et al., The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis. Angiogenesis, 2010. 13(3): p. 259-67.
[2].  Kathawala, R.J., et al., The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study. Oncotarget, 2015. 6(1): p. 510-21.
[3].  Becerikli, M., et al., EPHB4 tyrosine-kinase receptor expression and biological significance in soft tissue sarcoma. Int J Cancer, 2015. 136(8): p. 1781-91.

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References on NVP-BHG712

The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study.[Pubmed:25402202]

Oncotarget. 2015 Jan 1;6(1):510-21.

Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. Here, we determine the effect of NVP-BHG712, a specific EphB4 receptor inhibitor, on 1) paclitaxel resistance in HEK293 cells transfected with ABCC10, 2) the growth of tumors in athymic nude mice that received NVP-BHG712 and paclitaxel systemically and 3) the pharmacokinetics of paclitaxel in presence or absence of NVP-BHG712. NVP-BHG712 (0.5 muM), in HEK293/ABCC10 cells, significantly enhanced the intracellular accumulation of paclitaxel by inhibiting the efflux activity of ABCC10 without altering the expression level of the ABCC10 protein. Furthermore, NVP-BHG712 (25 mg/kg, p.o., q3d x 6), in combination with paclitaxel (15 mg/kg, i.p., q3d x 6), significantly inhibited the growth of ABCC10-expressing tumors in athymic nude mice. NVP-BHG712 administration significantly increased the levels of paclitaxel in the tumors but not in plasma compared to paclitaxel alone. The combination of NVP-BHG712 and paclitaxel could serve as a novel and useful therapeutic strategy to attenuate paclitaxel resistance mediated by the expression of the ABCC10 transporter.

The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis.[Pubmed:20803239]

Angiogenesis. 2010 Sep;13(3):259-67.

EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein-protein interaction domains and phosphorylation motifs of the ephrin ligands. Therefore, interfering with EphR/ephrin signaling by the means of targeted gene ablation, soluble receptors, dominant negative mutants or antisense molecules often does not allow to discriminate between inhibition of Eph/ephrin forward and reverse signaling. We developed a specific small molecular weight kinase inhibitor of the EphB4 kinase, NVP-BHG712, which inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. Furthermore, NVP-BHG712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration. In vivo, NVP-BHG712 inhibits VEGF driven vessel formation, while it has only little effects on VEGF receptor (VEGFR) activity in vitro or in cellular assays. The data shown here suggest a close cross talk between the VEGFR and EphR signaling during vessel formation. In addition to its established function in vascular remodeling and endothelial arterio-venous differentiation, EphB4 forward signaling appears to be an important mediator of VEGF induced angiogenesis since inhibition of EphB4 forward signaling is sufficient to inhibit VEGF induced angiogenesis.

Podocyte EphB4 signaling helps recovery from glomerular injury.[Pubmed:22398409]

Kidney Int. 2012 Jun;81(12):1212-25.

Eph receptor tyrosine kinases and their ligands (ephrins) have a pivotal role in the homeostasis of many adult organs and are widely expressed in the kidney. Glomerular diseases beginning with mesangiolysis can recover, with podocytes having a critical role in this healing process. We studied here the role of Eph signaling in glomerular disease recovery following mesangiolytic Thy1.1 nephritis in rats. EphB4 and ephrinBs were expressed in healthy glomerular podocytes and were upregulated during Thy1.1 nephritis, with EphB4 strongly phosphorylated around day 9. Treatment with NPV-BHG712, an inhibitor of EphB4 phosphorylation, did not cause glomerular changes in control animals. Nephritic animals treated with vehicle did not have morphological evidence of podocyte injury or loss; however, application of this inhibitor to nephritic rats induced glomerular microaneurysms, podocyte damage, and loss. Prolonged NPV-BHG712 treatment resulted in increased albuminuria and dysregulated mesangial recovery. Additionally, NPV-BHG712 inhibited capillary repair by intussusceptive angiogenesis (an alternative to sprouting angiogenesis), indicating a previously unrecognized role of podocytes in regulating intussusceptive vessel splitting. Thus, our results identify EphB4 signaling as a pathway allowing podocytes to survive transient capillary collapse during glomerular disease.

Description

NVP-BHG712 is an oral active EphB4 kinase autophosphorylation inhibitor, with IC50 values of 3.3 nM and 3.0 nM for EphA2 and EphB4, respectively.

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