NVP-BSK805ATP-competitive JAK2 inhibitor CAS# 1092499-93-8 |
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Quality Control & MSDS
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| Cas No. | 1092499-93-8 | SDF | Download SDF |
| PubChem ID | 57339395 | Appearance | Powder |
| Formula | C27H28F2N6O | M.Wt | 490.55 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | BSK 805 | ||
| Solubility | >20.95mg/mL in DMSO | ||
| Chemical Name | 4-[[2,6-difluoro-4-[3-(1-piperidin-4-ylpyrazol-4-yl)quinoxalin-5-yl]phenyl]methyl]morpholine;dihydrochloride | ||
| SMILES | C1CNCCC1N2C=C(C=N2)C3=NC4=C(C=CC=C4N=C3)C5=CC(=C(C(=C5)F)CN6CCOCC6)F.Cl.Cl | ||
| Standard InChIKey | NUOCAPALWRHKCU-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C27H28F2N6O.2ClH/c28-23-12-18(13-24(29)22(23)17-34-8-10-36-11-9-34)21-2-1-3-25-27(21)33-26(15-31-25)19-14-32-35(16-19)20-4-6-30-7-5-20;;/h1-3,12-16,20,30H,4-11,17H2;2*1H | ||
| 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. |
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| 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. |
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| 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. | ||
| Description | NVP-BSK805 is a potent and selective ATP-competitive inhibitor of JAK2 with IC50 of 0.5 nM,>20-fold selectivity towards JAK1, JAK3 and TYK2. | |||||
| Targets | JAK2 | |||||
| IC50 | 0.5 nM | |||||
NVP-BSK805 Dilution Calculator
NVP-BSK805 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.0385 mL | 10.1926 mL | 20.3853 mL | 40.7706 mL | 50.9632 mL |
| 5 mM | 0.4077 mL | 2.0385 mL | 4.0771 mL | 8.1541 mL | 10.1926 mL |
| 10 mM | 0.2039 mL | 1.0193 mL | 2.0385 mL | 4.0771 mL | 5.0963 mL |
| 50 mM | 0.0408 mL | 0.2039 mL | 0.4077 mL | 0.8154 mL | 1.0193 mL |
| 100 mM | 0.0204 mL | 0.1019 mL | 0.2039 mL | 0.4077 mL | 0.5096 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. | |||||
Abstract
The combination of two JAK2 inhibitors, NVP-BSK805 and NVP-BVB808, synergistically inhibited proliferation and induced apoptosis in cell lines with BCR-ABL or mutant JAK2, where reduced proliferation with a half-maximal growth-inhibitory value of 1 μM was observed in all BCR-ABL-positive cell lines. The combination of NVP-BSK805 and imatinib also showed a protective effect on those cells.
Abstract
NVP-BSK805, an orally available and selective inhibitor of JAK2, reduces constitutive STAT5 phosphorylation, suppresses cell proliferation and induces apoptosis in JAK2(V617F)-bearing cells. NVP-BSK805 suppressed leukemic cell spreading, splenomegaly, recombinant human erythropoirtin-induced polycythemia and extramedullary erythropoirsis in mice.
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NVP-BSK805 is a potent and selective inhibitor of JAK2 with IC50 value of 0.58 nM [1].
Janus kinase 2 (JAK2) is a member of the JAK family and is a non-receptor tyrosine kinase. JAK2 regulates signal transduction in the cell nucleus via activation of signal transducers and activators of transcription proteins (STATs), which form dimers upon phosphorylation and migrate into the nucleus to regulate the activation of target genes [2].
In JAK radiometric filter binding kinase assays, NVP-BSK805 inhibited full-length JAK2 wild-type and JAK2V617F enzymes with IC50 values of 0.58 nM and 0.56 nM, respectively [1]. In CHRF-288-11, SET-2 and HEL cells which expressed JAK2, NVP-BSK805 inhibited STAT5a phosphorylation [2].
In SCID beige mice injected with JAK2V617F-dependent Ba/F3 cells, NVP-BSK805 (150 mg/kg) suppressed STAT5 phosphorylation in spleen extracts by nearly 50% relative to vehicle-treated controls at the 6- and 12-hour time. In rats injected with recombinant human erythropoietin (rhEpo), which induced transient polycythemia and splenomegaly, NVP-BSK805 suppressed rhEpo-induced STAT5 phosphorylation in spleen in a dose-dependent way [1].
References:
[1]. Baffert F, Régnier CH, De Pover A, et al. Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805. Mol Cancer Ther, 2010, 9(7): 1945-1955.
[2]. Ringel F, Kaeda J, Schwarz M, et al. Effects of Jak2 type 1 inhibitors NVP-BSK805 and NVP-BVB808 on Jak2 mutation-positive and Bcr-Abl-positive cell lines. Acta Haematol, 2014, 132(1): 75-86.
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Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805.[Pubmed:20587663]
Mol Cancer Ther. 2010 Jul;9(7):1945-55.
The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2(V617F) mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2(V617F) and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2(V617F)-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2(V617F) cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats.
Effects of Jak2 type 1 inhibitors NVP-BSK805 and NVP-BVB808 on Jak2 mutation-positive and Bcr-Abl-positive cell lines.[Pubmed:24504330]
Acta Haematol. 2014;132(1):75-86.
Janus kinases are critical components of signaling pathways that regulate hematopoiesis. Mutations of the non-receptor tyrosine kinase JAK2 are found in many BCR-ABL-negative myeloproliferative neoplasms. Preclinical results support that JAK2 inhibitors could show efficacy in treating chronic myeloproliferative neoplasms. JAK2 has also been postulated to play a role in BCR-ABL signal transduction. Therefore, inhibitors of JAK2 kinases are turning into therapeutic strategies for treatment of chronic myelogenous leukemia (CML). In this study, the effects of two novel JAK2 inhibitors, NVP-BSK805 and NVP-BVB808, have been investigated in cell lines expressing either BCR-ABL or mutant JAK2. Possible synergies between NVP-BSK805/NVP-BVB808 and the kinase inhibitors imatinib and nilotinib were assessed. Proliferation and apoptosis tests with both substances showed response in the following cell lines: CHRF-288-11, SET-2 and UKE-1. All BCR-ABL-positive cell lines showed some reduction in proliferation, but with half-maximal growth-inhibitory values >1 microM. Combination of the JAK2 inhibitors with imatinib and nilotinib showed no significant additive or synergistic effects, although all BCR-ABL-positive cell lines responded well to both CML therapeutic agents. Interestingly, it seemed that the combination of imatinib with NVP-BSK805 had a protective effect on the cells. Combination treatment with nilotinib did not show this effect.
