Ralimetinib dimysylate (LY2228820 dimysylate)

Alias: LY-2228820; LY 2228820; Ralimetinib; LY2228820; LY2228820 dimesylate; Ralimetinib dimesylate
Cat No.:V0479 Purity: ≥98%
Ralimetinib dimysylate (also known as LY-2228820; LY2228820) is a novel, potent and selective ATP-competitive inhibitor of p38 MAPK with potential anti-inflammatory activity.
Ralimetinib dimysylate (LY2228820 dimysylate) Chemical Structure CAS No.: 862507-23-1
Product category: p38 MAPK
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Ralimetinib dimysylate (LY2228820 dimysylate):

  • Ralimetinib ( LY2228820)
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Ralimetinib dimysylate (also known as LY-2228820; LY2228820) is a novel, potent and selective ATP-competitive inhibitor of p38 MAPK with potential anti-inflammatory activity. In a cell-free assay, it inhibits p38 MAPK with an IC50 of 7 nM and does not affect p38 MAPK activation. In cell-based assays, LY2228820 potently and selectively inhibited phosphorylation of MK2 (Thr334) in anisomycin-stimulated HeLa cells (at 9.8 nmol/L by Western blot analysis) and anisomycin-induced mouse RAW264.7 macrophages (IC(50) = 35.3 nmol/L) with no changes in phosphorylation of p38α MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc ≤ 10 μmol/L.

Biological Activity I Assay Protocols (From Reference)
Targets
p38β MAPK (IC50 = 3.2 nM); p38α MAPK (IC50 = 5.8 nM)
ln Vitro
Ralimetinib dimesylate inhibits p38α and the quantity of phosphoMAPKAPK-2 (pMK2) in RAW 264.7 cells with IC50 values of 7 nM and 34.3 nM, respectively. Additionally, Ralimetinib dimesylate inhibits lipopolysaccharide (LPS)-induced TNFα synthesis in murine peritoneal macrophages with an IC50 of 5.2 nM[1]. Ralimetinib dimesylate (LY2228820) (200 nM-800 nM) significantly inhibits p38MAPK signaling in multiple myeloma (MM) cells, including INA6, RPMI-8226, U266 and RPMI-Dox40, as shown by its inhibition on phosphorylation of HSP27, a downstream target of p38MAPK, without changing the expression level of HSP27. Ralimetinib dimesylate (200 nM–400 nM) increases bortezomib-induced cytotoxicity and apoptosis, but Ralimetinib dimesylate alone does not inhibit the growth of MM.1S cells. Additionally, ralimetinib dimesylate (200 nM-800 nM) inhibits the release of IL-6 and MIP-1 from long-term BM stromal cells (LT-BMSCs), BM mononuclear cells (BMMNCs), and peripheral blood (PB) CD138+, CD138-, or PB CD14+ cells. Additionally, osteoclastogenesis from CD14+ cells is prevented by ralimetinib dimesylate (400 nM–800 nM)[2].
ln Vivo
Ralimetinib dimesylate inhibits the production of TNFα in LPS-induced mice with a threshold minimum 50% effective dose (TMED50) of less than 1 mg/kg. Ralimetinib dimesylate exhibits strong effects on paw swelling, bone deterioration, and cartilage destruction in a rat model of collagen-induced arthritis (CIA), with a threshold minimum 50% effective dose (TMED50) of 1.5 mg/kg[1]. In mice implanted with B16-F10 melanoma, ralimetinib dimesylate inhibits tumor phospho-MK2 in a dose-dependent manner (TED50=1.95 mg/kg, TED70=11.17 mg/kg). Mouse in vivo TED50=1.01 mg/kg (compound exposure approximately 100 nM) and human ex vivo IC50=0.12 μM with either mouse or human PBMC[3] are the values for ralimetinib dimesylate's ability to inhibit MK2 phosphorylation.
Enzyme Assay
Inhibition of p38α is determined using recombinant human p38α in a standard filter binding protocol using ATP[γ-33P] and EGFR 21-mer peptide as substrate. Functional inhibition of TNFα in murine peritoneal macrophages is determined using LPS stimulation in the presence of LY2228820. To assess p38α activity in cells more directly, RAW 264.7 cells are treated with LY2228820 and then stimulated with anisomycin. The level of p38α activity is detected using a phosphoMAPKAPK-2 (pMK2) (Thr 334) antibody which reacts with a residue specifically phosphorylated by p38α.
Cell Assay
Recombinant human p38α is used in a standard filter binding protocol with ATP[γ-33P] and the EGFR 21-mer peptide as substrate to measure the inhibition of p38. Using LPS stimulation and Ralimetinib, the functional inhibition of TNFα in murine peritoneal macrophages is assessed. RAW 264.7 cells are given ralimetinib treatment before being stimulated with anisomycin in order to more accurately measure p38α activity in the cells. A phosphoMAPKAPK-2 (pMK2) (Thr 334) antibody that reacts with a residue that has been specifically phosphorylated by p38 is used to measure the level of p38α activity.
Animal Protocol
Murine B16-F10 melanoma cells are cultured in Dulbecco's Modified Eagle Medium with l-glutamine, high glucose, and 10% FBS (GIBCO 11965-092). B16-F10 cells (2×106) are implanted into the rear flank of C57/bl6 mice, and when the tumors grow to a size of about 200 mm3, Ralimetinib dimesylate in 1% carboxymethylcellulose/0.25% Tween 80 is given orally. Tumors are removed, homogenized, and lysed two hours after the dose for Western blot analysis. Chemiluminescent detection is used to measure MK2 phosphorylation (p-Thr334), which is normalized to total glyceraldehyde-3-phosphate dehydrogenase. In xenograft models, the 50% or 70% threshold effective dose (TED50 and TED70, respectively) is calculated to approximate the effective dose ranges where significant target inhibition is seen. The TED50 or TED70 is the dose at which a statistically significant effect is obtained and there is at least 50% or 70% inhibition, in comparison to the vehicle control, respectively.
References

[1]. Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38alpha MAP kinase inhibitors with excellent in vivo antiinflammatory properties. Bioorg Med Chem Lett, 2008, 18(1), 179-183.

[2]. p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications. Br J Haematol, 2008, 141(5), 598-606.

[3]. Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol Cancer Ther. 2014 Feb;13(2):364-74.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C24H29FN6.2CH4O3S
Molecular Weight
612.74
Elemental Analysis
C, 50.97; H, 6.09; F, 3.10; N, 13.72; O, 15.67; S, 10.46
CAS #
862507-23-1
Appearance
Solid powder
SMILES
CC(C)(C)CN1C2=C(C=CC(=N2)C3=C(N=C(N3)C(C)(C)C)C4=CC=C(C=C4)F)N=C1N.CS(=O)(=O)O.CS(=O)(=O)O
InChi Key
NARMJPIBAXVUIE-UHFFFAOYSA-N
InChi Code
InChI=1S/C24H29FN6.2CH4O3S/c1-23(2,3)13-31-20-17(28-22(31)26)12-11-16(27-20)19-18(14-7-9-15(25)10-8-14)29-21(30-19)24(4,5)6;2*1-5(2,3)4/h7-12H,13H2,1-6H3,(H2,26,28)(H,29,30);2*1H3,(H,2,3,4)
Chemical Name
5-[2-tert-butyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-3-(2,2-dimethylpropyl)imidazo[4,5-b]pyridin-2-amine;methanesulfonic acid
Synonyms
LY-2228820; LY 2228820; Ralimetinib; LY2228820; LY2228820 dimesylate; Ralimetinib dimesylate
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~4 mg/mL warmed (~6.5 mM)
Water: ~100 mg/mL (~163.2 mM)
Ethanol: ~3 mg/mL (~4.9 mM)
Solubility (In Vivo)
Saline: 30mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.6320 mL 8.1601 mL 16.3201 mL
5 mM 0.3264 mL 1.6320 mL 3.2640 mL
10 mM 0.1632 mL 0.8160 mL 1.6320 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

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Biological Data
  • LY2228820

  • LY2228820
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