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Neflamapimod (VX-745)

Neflamapimod (VX-745)

ArtNr	S1458-10
Hersteller	Selleckchem
CAS-Nr.	209410-46-8
Menge	10 mg
Kategorie	Oncology Neuroscience Neuroinflammation Metabolism Diabetes Glucose Homeostasis Inhibitors & Compound Libraries Small Molecules By Organ Bladder Cancer Lymphatic System Cancer Bone Cancer
Typ	Inhibitors
Specific against	other
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	p38alpha MAPK, p38beta MAPK;p38 MAPK
Similar products	VX-745
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Administration	Oral gavage twice daily
Animal Models	Type II collagen-induced arthritis (CIA) mice model (DBA/1J)
Cell lines	Human bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells
Chemical Name	5-(2, 6-dichlorophenyl)-2-(2, 4-difluorophenylthio)-6H-pyrimido[1, 6-b]pyridazin-6-one
Concentrations	60 nM - 20 uM, dissolved in DMSO.
Description	VX-745 is a potent and selective inhibitor of p38alpha MAPK and p38beta MAPK with IC50 of 10 nM and 220 nM, respectively.
Dosages	2.5, 5, and 10 mg/kg
Features	VX-745 is a potent and selective inhibitor to p38alpha and p38beta MAPK.
Formulation	Dissolved in 100% polyethylene glycol
IC50	10 nM [1], 10 nM [1], 10 nM [1], 10 nM [1], 10 nM [1], 10 nM [1]
In vitro	VX-745 selectively inhibits p38alpha and p38beta MAPK with IC50 of 10 nM and 220 nM, respectively, but not p38gamma MAPK and a large panel of other kinases, with IC50 larger than 20 uM. In a human peripheral blood mononuclear cell (PBMC) assay, VX-745 provides IC50 of 56 and 52 nM for IL-1beta and TNFalpha, respectively. VX-745 blocks IL-6 and IL-8 production induced by IL-1 and TNFalpha, and COX-2 synthesis mediated by LPS and IL-1beta. [1-3] VX-745 (60 nM–20 uM) inhibits IL-6 and VEGF secretion in bone marrow stromal cells (BMSCs), without affecting their viability. VX-745 also inhibits TNF-alpha–induced IL-6 secretion in BMSCs. VX-745 inhibits both multiple myeloma (MM) cell proliferation and IL-6 secretion in BMSCs triggered by adherence of MM cells to BMSCs, suggesting that VX-745 can inhibit paracrine multiple myeloma (MM) cell growth in the BM milieu and overcome cell adhesion-related drug resistance. [4]
In vivo	VX-745 is effective against adjuvant-induced arthritis (AA) in the rat with ED50 of 5 mg/kg. Histological scores for VX-745 in AA rats are 93% inhibition of bone resorption and 56% inhibition of inflammation. In the classical cartilage-induced arthritis model, VX-745 exhibits a dose-responsive decrease in severity score. [1-3] In a type II collagen-induced arthritis (CIA) mice model, VX-745 (2.5, 5, and 10 mg/kg) has 27%, 31%, and 44% improvement in the inflammatory scores, respectively, when compared to vehicle-treated mice. In addition, histological scores show a 32–39% protection of bone and cartilage erosion by VX-745. [5]
Incubation Time	48 hours
Kinase Assay	[5], Spectrophotometric coupled-enzyme assay, The IC50 for the inhibition of p38alpha and p38beta homologs are obtained by a spectrophotometric coupled-enzyme assay. A fixed concentration of enzyme (15 nM of p38alpha or p38beta) is incubated with VX-745 in DMSO for 10 min. at 30 C in 0.1 M HEPES buffer, pH 7.5, containing 10% glycerol, 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 uM NADH, 150 ug/mL pyruvate kinase, 50 ug/mL lactate dehydrogenase, and 200 uM EGF receptor peptide (KRELVEPLTPSGEAPNQALLR). The reaction is initiated with 100 uM and 70 uM ATP for p38alpha and p38beta assays, respectively. The decrease of absorbance at 340 nm is monitored to follow the rate of the reaction. IC50 is evaluated from the rate data as a function of the inhibitor concentration.
Method	BMSCs (5 x 104 cells/well) or MM cells (3 x 104 cells/well) are incubated in 96-well culture plates in the presence or absence of VX-745 for 48 hours at 37 C. DNA synthesis is measured by [3H]-thymidine ([3H]TdR) uptake. Cells are pulsed with [3H]TdR (0.5 uCi/well [.0185 MBq]) during the last 8 hours of 48-hour cultures. Growth inhibition of both MM cells and BMSCs by VX-745 is also assessed by measuring 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) dye absorbance.
Molecular Weight (MW)	436, 26
Picture ChemicalStructure Description	VX-745 Chemical Structure
Solubility (25C)	DMSO 15 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL
Storage	2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO

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