Home MAPK p38 MAPK inhibitor Neflamapimod (VX-745)

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Neflamapimod (VX-745) p38 MAPK inhibitor

Cat.No.S1458

Neflamapimod (VX-745) is a potent and selective inhibitor of p38α with IC50 of 10 nM, exhibiting 22-fold greater selectivity versus p38β and no inhibition to p38γ.
Neflamapimod (VX-745) p38 MAPK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 436.26

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Chemical Information, Storage & Stability

Molecular Weight 436.26 Formula

C19H9Cl2F2N3OS

 Storage (From the date of receipt)
CAS No. 209410-46-8 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles C1=CC(=C(C(=C1)Cl)C2=C3C=CC(=NN3C=NC2=O)SC4=C(C=C(C=C4)F)F)Cl

Solubility

In vitro
Batch:

DMSO : 15 mg/mL (34.38 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Features
A potent and selective inhibitor to p38α and p38β MAPK.
Targets/IC50/Ki
p38α [1]
10 nM
p38β [1]
220 nM
In vitro
Neflamapimod (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, it provides IC50 of 56 and 52 nM for IL-1β and TNFα, respectively. This compound 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] At concentrations of 60 nM-20 µM, it inhibits IL-6 and VEGF secretion in bone marrow stromal cells (BMSCs), without affecting their viability. It also inhibits TNF-α-induced IL-6 secretion in BMSCs. Furthermore, it 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]
Kinase Assay
Spectrophotometric coupled-enzyme assay
Neflamapimod (VX-745) 的 IC50 值通过分光光度法偶联酶测定获得，用于抑制 p38α 和 p38β 同源蛋白。将固定浓度的酶（15 nM p38α 或 p38β）与该化合物在 DMSO 中于 30 °C 孵育 10 分钟，缓冲液为 0.1 M HEPES（pH 7.5），含 10% 甘油、10 mM MgCl2、2.5 mM 磷酸烯醇丙酮酸、200 µM NADH、150 µg/mL 丙酮酸激酶、50 µg/mL 乳酸脱氢酶和 200 µM EGF 受体肽（KRELVEPLTPSGEAPNQALLR）。反应分别通过加入 100 µM（p38α 测定）和 70 µM（p38β 测定）的 ATP 启动。通过监测 340 nm 处吸光度的降低来跟踪反应速率，IC50 值根据速率数据随该抑制剂浓度的函数关系评估得出。
In vivo
Neflamapimod (VX-745) is effective against adjuvant-induced arthritis (AA) in the rat with ED50 of 5 mg/kg. Histological scores for this compound in AA rats are 93% inhibition of bone resorption and 56% inhibition of inflammation. In the classical cartilage-induced arthritis model, it 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 it. [5]
References
  • [4] https://pubmed.ncbi.nlm.nih.gov/12393542/
  • [5] http://pubs.acs.org/doi/abs/10.1021/ml2001455

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02423200 Completed
Alzheimer''s Disease
EIP Pharma Inc
 April 2015 Phase 2

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