VX-745 is a lead anti-inflammatory candidate, p38 MAPK inhibitor (IC50=10 nM) for the treatment of Rheumatoid arthritis (RA). p38 MAPK is a specific enzyme that regulates the production of IL-1, IL-2, IL-6, TNFα, chemokines and nitric oxide (NO), as part of acute and chronic inflammatory responses. In vitro, VX-745 was selective for p38 MAPK compared to a large panel of kinases (IC50≥20µM). VX-745 selectively inhibited p38α MAPK (IC50=10 nM), p38β MAPK (IC50 =220 nM) , but not p38γ MAPK (IC50≥20 µM). In addition, cell data for VX-745 provided IC50 values of 56 and 52 nM for IL-1β and TNFα, respectively, and VX-745 blocked IL-6 and IL-8 production induced by IL-1 and TNFα. In a human whole blood assay, IC50 values were 152 and 177 nM for IL-1β and TNFα inhibition, respectively.
|Cell lines||Human bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells|
|Preparation method||Incubating BMSCs (5 × 104 cells/well) or MM cells (3 × 104 cells/well) in 96-well culture plates in the presence or absence of VX-745 for 48 hours at 37 °C. Measuring DNA synthesis by [3H]-thymidine ([3H]TdR) uptake. Cells are pulsed with [3H]TdR (0.5 μCi/well [.0185 MBq]) during the last 8 hours of 48-hour cultures. Measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) dye absorbance to assess growth inhibition of both MM cells and BMSCs by VX-745 .|
|Concentrations||60 nM - 20 μM, dissolved in DMSO.|
|Incubation time||48 hours|
|Animal models||Type II collagen-induced arthritis (CIA) mice model (DBA/1J)|
|Formulation||Dissolved in 100% polyethylene glycol|
|Dosages||2.5, 5, and 10 mg/kg|
|Administration||Oral gavage twice daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 10 mg/mL|
|Related p38 MAPK Products|
SB 239063 is a potent and selective p38 MAPK inhibitor (IC50 = 44 nM for p38α). SB 239063 displays > 220-fold selectivity over ERK, JNK1 and other kinases; ~ 3-fold more selective than SB 203580.
SD-06 is a p38 MAP kinase inhibitor; inhibits p38α with an IC50 value of 170 nM and inhibits LPS-stimulated TNF-release in rats (83% inhibition at 1mg/kg, po). IC50 value: 170 nM Target: p38MAPK
SKF-86002 is a potent inhibitor of p38 MAP kinase wit IC50 of 0.5-1 uM; inhibits LPS-induced IL-1 and TNF-α production in human monocytes.
TA-02 is a p38 MAPK inhibitor with IC50 of 20 nM. IC50 value: 20 nM. TA-02 is a novel compound with similar cardiogenic properties as SB203580 and SB202190. TA-02 especially inhibits TGFBR-2.
Pexmetinib (ARRY-614) is a potent, orally bioavailable, dual p38 MAPK/Tie-2 inhibitor with IC50 of 4 nM/18 nM in a HEK-293 cell line. Phase 1.
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