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NVP-BSK805 2HClJAK2 inhibitor

NVP-BSK805 2HCl

Catalog No. A4148
Size Price Stock Qty
5mg $170.00 In stock
10mg $230.00 In stock
50mg $590.00 In stock
200mg $1,690.00 In stock

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Worldwide Distributors

Sample solution is provided at 25 µL, 10mM.

Quality Control

Chemical structure

NVP-BSK805 2HCl

Protocol

Cell experiment [1]:

Cell lines

JAK2V617F-mutant SET-2 cells

Preparation method

The solubility of this compound in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

1 μmol/L, 24 and 48 h

Applications

NVP-BSK805 blocked the growth of JAK2V617F cells and induced apoptosis with GI50 of <100 nmol/L. NVP-BSK805 induced apoptosis in JAK2V617F-mutant SET-2 cells in a dose- and time-dependent manner. NVP-BSK805 potently suppressed STAT5 phosphorylation in JAK2V617F mutant cell lines and displayed a bias for JAK2 over JAK1 and JAK3 inhibition.

Animal experiment [1]:

Animal models

Ba/F3 JAK2V617F-luc mouse model, Mouse rhEpo-induced polycythemia model

Dosage form

Oral administration, 150 mg/kg

Application

NVP-BSK805 (150 mg/kg) suppressed STAT5 phosphorylation, splenomegaly, and leukemic cell spreading in a Ba/F3 JAK2V617F cell–driven mouse model. NVP-BSK805 suppressed rhEpo-induced STAT5 phosphorylation as well as rhEpo-mediated polycythemia and splenomegaly in BALB/c mice.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Baffert F, Régnier C H, De Pover A, et al. Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805[J]. Molecular cancer therapeutics, 2010, 9(7): 1945-1955.

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Chemical Properties

Cas No. 1092499-93-8 SDF Download SDF
Chemical Name 4-[[2,6-difluoro-4-[3-(1-piperidin-4-ylpyrazol-4-yl)quinoxalin-5-yl]phenyl]methyl]morpholine;dihydrochloride
Canonical SMILES C1CNCCC1N2C=C(C=N2)C3=NC4=C(C=CC=C4N=C3)C5=CC(=C(C(=C5)F)CN6CCOCC6)F.Cl.Cl
Formula C27H28F2N6O.2HCl M.Wt 563.47
Solubility Soluble in DMSO > 10 mM Storage Store at -20°C
General tips N/A
Shipping Condition N/A

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Background

NVP-BSK805 2HCl is a potent and selective ATP-competitive inhibitor of JAK2 [1].

Janus kinase 2 (JAK2), a non-receptor tyrosine kinase, is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptorfamily, the GM-CSF receptor family, the gp130 receptor family, and the single chain receptors[2].

In vitro: NVP-BSK805 potently inhibited JAK2, displaying more than 20-fold selectivity towards JAK1, JAK3, and TYK2. In an internal kinase panel, NVP-BSK805 showed potent inhibition of JAK2, along with good selectivity towards the other three JAK family members, indicating the fairly selectivity against other kinases. NVP-BSK805 is an ATP-competitive inhibitor with the Ki values of 0.43 ± 0.02 nmol/L. In Ba/F3 cell-based assays of JAK2V617F dependency and a panel of JAK2V617F-bearing acute myeloid leukemia cell lines derived from patients with a history of cMPNs, NVP-BSK805 exhibited half-maximal growth inhibition (GI50) at concentrations < 100 nmol/L. In K-562 cells, NVP-BSK805 suppressed growth with the GI50 value of 1.5 μmol/L. In CMK cells, the GI50value of NVP-BSK805 was about 2 μmol/L. Incubation of SET-2 cells with 150 nM and 1 μM of NVP-BSK805, which corresponds to concentration yielding 75% and 95% growth inhibition, respectively, for 24, 48, and 72 hours lead to concentration- and time- dependent induction of apoptosis[1]. In both SET-2 and MB-02 cells,NVP-BSK805 triggered cell death required activation of caspase cascades and was overcome by caspase inhibition. NVP-BSK805 modulated the post-translational modification of Bim and levels of Mcl-1 in JAK2V617F cells, SET-2 and MB-02 cells[3].

In vivo: Oral bioavailability of NVP-BSK805 in mice was estimated to be 45%, while 50% in rats. In a Ba/F3 JAK2V617F cell–driven mouse model, Oral administration of NVP-BSK805 (150 mg/kg) suppressed STAT5 phosphorylation, splenomegaly, and leukemic cell spreading. In BALB/c mice, NVP-BSK805 suppressedrhEpo-induced STAT5 phosphorylation as well as rhEpo-mediated polycythemia and splenomegaly at doses of 25, 50, and 100 mg/kg orally [1].

References:
[1] Baffert F, Régnier C H, De Pover A, et al.  Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805[J]. Molecular cancer therapeutics, 2010, 9(7): 1945-1955.
[2] Bole-Feysot C, Goffin V, Edery M, et al.  Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice[J]. Endocrine reviews, 1998, 19(3): 225-268.
[3] Rubert J, Qian Z, Andraos R, et al.  Bim and Mcl-1 exert key roles in regulating JAK2 V617F cell survival[J]. BMC cancer, 2011, 11(1): 1.