product name Decernotinib (VX-509)
Description: Decernotinib, also known as VX-509 or VRT-831509 or adelatinib, is a potent and selective JAK3 inhibitor with Ki of 2.5 nM, >4-fold selectivity over JAK1, JAK2, and TYK2, respectively. Decernotinib is an oral, selective Janus kinase 3 (JAK3) inhibitor being developed by Vertex. VX-509 may represent a new approach to treating an underlying disease mechanism that triggers inflammation in a number of debilitating diseases, including RA. In immune-mediated diseases, JAK3 is an essential component of the immune signaling cascade. This cascade ultimately contributes to abnormal immune response that results in chronic inflammation and, in the case of RA, irreversible damage to cartilage and bones.
References: J Pharmacol Exp Ther. 2015 May;353(2):405-14; J Med Chem. 2015 Sep 24;58(18):7195-216.
392.38
Formula
C18H19F3N6O
CAS No.
944842-54-0
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 78 mg/mL (198.8 mM)
Water: <1 mg/mL
Ethanol: 20 mg/mL warmed (51.0 mM)
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
In vitro activity: In HT-2 cells, Decernotinib inhibits IL-2–stimulated HT-2 STAT-5 phosphorylation, human T-cell blast proliferation, and CD40L/IL-4–induced B-cell proliferation. Kinase Assay: The effect of VX-509 on JAK3 activity is assessed by measuring the residual kinase activity of the recombinantly expressed JAK3 kinase domain using a radiometric assay. The final concentrations of the components in the assay are as follows: 100 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM dithiothreitol (DTT), 0.01% BSA, 0.25 nM JAK3, 0.25 mg/ml polyE4Y, and 5 μM 33P-γ-ATP (200 µCi/µmol). A 10 mM stock solution of VX-509 is prepared in DMSO, from which additional dilutions are prepared. A substrate mixture (100 mM HEPES, 10 mM MgCl2, 0.5 mg/ml polyE4Y, and 10 μM 33P-γ-ATP) is added and mixed with VX-509 stock solution. The reaction is initiated by the addition of an enzyme mixture [100 mM HEPES (pH 7.5), 10 mM MgCl2, 2 mM DTT, 0.02% BSA, 0.5 nM JAK3]. After 15 minutes, the reaction was quenched with 20% trichloroacetic acid (TCA). The quenched reaction was transferred to the GF/B filter plates and washed three times with 5% TCA. Following the addition of Ultimate Gold scintillant (50 μl), the samples were counted in a Packard TopCount gamma counter (PerkinElmer). In this procedure, the radioactivity trapped is a measure of the residual JAK3 kinase activity. From the activity versus concentration of VX-509 titration curve, the Ki value was determined by fitting the data to an equation for competitive tight binding inhibition kinetics using Prism software. Cell Assay: Frozen purified human B cells atr thawed, washed, and resuspended in complete medium. Cells are plated onto a 96-well plate at a density of 2 × 105 cells/well. VX-509 is added, and plates are incubated for 30 minutes at 37°C, followed by stimulation with a combination of 10 ng/ml IL-4 and 1 μg/ml CD40L. DMSO alone is added to the top two rows, one of which is stimulated with IL-4 or CD40L (negative control) and the other of which served as a proliferation control. The plates are incubated at 37°C for 6 days. On day 6, cells are pulsed with [3H]thymidine for 7 hours and harvested onto filters for radioactive determination using a PerkinElmer-Wallace beta counter (1205 Betaplate Beta Liquid Scintillation Counter). Data are analyzed with Softmax pro software to generate an IC50 value. |
|---|---|
| In Vivo | In a rat model of collagen-induced arthritis, VX-509 (50 mg/kg, p.o.) results in dose-dependent reduction in ankle swelling and paw weight and improved paw histopathology scores. In a mouse model of oxazolone-induced delayed-type hypersensitivity, VX-509 (50 mg/kg, p.o.) significantly suppresses ear edema. In a rat HvG model, VX-509 (50 mg/kg, p.o.) results in dose-dependent inhibition of popletial lymph node (PLN) hyperplasia. |
| Animal model | Collagen-induced arthritis (CIA) rat model |
| Formulation & Dosage | Dissolved in 10% vitamin E d-α-tocophenyl polyethylene glycol 1000 succinate and 1% hydroxypropyl methylcellulose acetyl succinate; 50 mg/kg; administrated orally |
| References | J Pharmacol Exp Ther. 2015 May;353(2):405-14; J Med Chem. 2015 Sep 24;58(18):7195-216. |
