Neflamapimod (VX-745)

Catalog No.S1458 Batch:S145801

Print

Technical Data

Formula

C19H9Cl2F2N3OS
Molecular Weight 436.26 CAS No. 209410-46-8
Solubility (25°C)* In vitro DMSO 15 mg/mL (34.38 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description Neflamapimod (VX-745) is a potent and selective inhibitor of p38α with IC50 of 10 nM, 22-fold greater selectivity versus p38β and no inhibition to p38γ.
Targets
p38α [1] p38β [1]
10 nM 220 nM
In vitro VX-745 selectively inhibits p38α and p38β MAPK with IC50 of 10 nM and 220 nM, respectively, but not p38γ MAPK and a large panel of other kinases, with IC50 larger than 20 µM. In a human peripheral blood mononuclear cell (PBMC) assay, VX-745 provides IC50 of 56 and 52 nM for IL-1β and TNFα, respectively. VX-745 blocks IL-6 and IL-8 production induced by IL-1 and TNFα, and COX-2 synthesis mediated by LPS and IL-1β. [1-3] VX-745 (60 nM-20 µM) inhibits IL-6 and VEGF secretion in bone marrow stromal cells (BMSCs), without affecting their viability. VX-745 also inhibits TNF-α-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]
Features A potent and selective inhibitor to p38α and p38β MAPK.

Protocol (from reference)

Kinase Assay:[5]
  • Spectrophotometric coupled-enzyme assay

    The IC50 for the inhibition of p38α and p38β homologs are obtained by a spectrophotometric coupled-enzyme assay. A fixed concentration of enzyme (15 nM of p38α or p38β) 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 µM NADH, 150 µg/mL pyruvate kinase, 50 µg/mL lactate dehydrogenase, and 200 µM EGF receptor peptide (KRELVEPLTPSGEAPNQALLR). The reaction is initiated with 100 µM and 70 µM ATP for p38α and p38β 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.
Cell Assay:[4]
  • Cell lines

    Human bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells

  • Concentrations

    60 nM - 20 μM, dissolved in DMSO.

  • Incubation Time

    48 hours

  • Method

    BMSCs (5 × 104 cells/well) or MM cells (3 × 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 μCi/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.
Animal Study:[5]
  • Animal Models

    Type II collagen-induced arthritis (CIA) mice model (DBA/1J)

  • Dosages

    2.5, 5, and 10 mg/kg

  • Administration

    Oral gavage twice daily

Customer Product Validation

Data from [Data independently produced by , , FASEB J, 2018, doi:10.1096/fj.201801977R]

Selleck's Neflamapimod (VX-745) has been cited by 13 publications

Konjac Ceramide (kCer)-Mediated Signal Transduction of the Sema3A Pathway Promotes HaCaT Keratinocyte Differentiation [ Biology (Basel), 2022, 11(1)121] PubMed: 35053118
TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria [ EMBO J, 2021, e106188] PubMed: 33881780
The Global Phosphorylation Landscape of SARS-CoV-2 Infection [ Cell, 2020, 182(3):685-712.e19] PubMed: 32645325
The Global Phosphorylation Landscape of SARS-CoV-2 Infection [ Cell, 2020, 182(3):685-712.e19] PubMed: 32645325
Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling [ Dev Cell, 2020, S1534-5807(20)30757-7] PubMed: 33080171
p38 MAPK signalling regulates cytokine production in IL-33 stimulated Type 2 Innate Lymphoid cells. [ Sci Rep, 2020, 10(1):3479] PubMed: 32103032
IL-33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3 [ Immunol Cell Biol, 2019, 97(1):54-71] PubMed: 30171775
Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy. [ J Pharmacol Exp Ther, 2019, 370(2):219-230] PubMed: 31189728
Activating β-catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK [Jie Z FASEB J, 2018, 10.1096/fj.201801977R] PubMed: 30526042
Differential control of Toll-like receptor 4-induced interleukin-10 induction in macrophages and B cells reveals a role for p90 ribosomal S6 kinases. [ J Biol Chem, 2018, 293(7):2302-2317] PubMed: 29229781

RETURN POLICY
Selleck Chemical’s Unconditional Return Policy ensures a smooth online shopping experience for our customers. If you are in any way unsatisfied with your purchase, you may return any item(s) within 7 days of receiving it. In the event of product quality issues, either protocol related or product related problems, you may return any item(s) within 365 days from the original purchase date. Please follow the instructions below when returning products.

SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

NOT FOR HUMAN, VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.