Ralimetinib (LY2228820) dimesylate

Catalog No.S1494 Batch:S149402

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Technical Data

Formula

C24H29FN6.2CH4O3S
Molecular Weight 612.74 CAS No. 862507-23-1
Solubility (25°C)* In vitro Water 100 mg/mL (163.2 mM)
Ethanol 20 mg/mL (32.64 mM)
DMSO 4 mg/mL (6.52 mM)
* <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.)

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Biological Activity

Description Ralimetinib (LY2228820) dimesylate is a novel and potent inhibitor of p38 MAPK with IC50 of 7 nM in a cell-free assay, does not alter p38 MAPK activation. Phase 1/2.
Targets
p38α [1]
(Cell-free assay)
7 nM
In vitro LY2228820 inhibits p38α, as well as the level of phosphoMAPKAPK-2 (pMK2) in RAW 264.7 cells, with IC50 values of 7 nM and 34.3 nM, respectively. Furthermore, LY2228820 inhibits lipopolysaccharide (LPS)-induced TNFα formation in murine peritoneal macrophages, with IC50 of 5.2 nM. [1] In multiple myeloma (MM) cells, including INA6, RPMI-8226, U266, and RPMI-Dox40, LY2228820 (200 nM–800 nM) significantly blocks p38MAPK signaling, as revealed by its inhibition on phosphorylation of HSP27, a downstream target of p38MAPK, without affecting the expression level of HSP27. LY2228820 (200 nM–400 nM) enhances bortezomib-induced cytotoxicity and apoptosis, but LY2228820 alone doesn't inhibit the growth of MM.1S cells. LY2228820 (200 nM–800 nM) also inhibits secretion of IL-6 and MIP-1α in long-term BM stromal cells (LT-BMSCs), BM mononuclear cells (BMMNCs), peripheral blood (PB) CD138+, CD138− or PB CD14+ cells. LY2228820 (400 nM–800 nM) also blocks osteoclastogenesis from CD14+ cells. [2]
In vivo In LPS-induced mice, LY2228820 effectively inhibits the formation of TNFα with a threshold minimum 50% effective dose (TMED50) less than 1 mg/kg. In a rat model of collagen-inducedarthritis (CIA), LY2228820 displays potent effects on paw swelling, bone erosion, and cartilage destruction, with a threshold minimum 50% effective dose (TMED50)of 1.5 mg/kg. [1]

Protocol (from reference)

Kinase Assay:[1]
  • Inhibition of p38α

    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:[2, 3]
  • Cell lines

    MM cells, including INA6, RPMI-8226, U266, and RPMI-Dox40

  • Concentrations

    200 nM–800 nM

  • Incubation Time

    48 hours

  • Method

    MTT assays and APO 2.7 staining are performed to assess cellular proliferation and induction of apoptosis, respectively. Viability is expressed as percent viable cells. Apoptosis in cells is evaluated by APO 2.7 staining. For detection of mitochondrial membrane protein 7A6 expressed in apoptotic cells, cells are incubated with APO 2.7 reagent for 20 min. Expression of APO 2.7 is determined using an EPICS XL flow cytometer.
Animal Study:[1]
  • Animal Models

    Lipopolysaccharide (LPS)-induced Balb/c mice

  • Dosages

    0–20 mg/kg

  • Administration

    Oral bid dosing for 14 days

Customer Product Validation

Data from [Data independently produced by Acta Pharmacol Sin, 2014, 35, 339-50]

Data from [Blood, 2012, 119, 6255-8]

Data from [Mol Cancer Ther, 2011, 10, 2244-56]

, , Dr. Yong-Weon Yi from Georgetown University Medical Center

Selleck's Ralimetinib (LY2228820) dimesylate has been cited by 80 publications

Transferrin receptor 2 mitigates periodontitis-driven alveolar bone loss [ J Cell Physiol, 2024, 10.1002/jcp.31172] PubMed: 38214117
Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor [ Cell Chem Biol, 2023, 30(10):1211-1222.e5] PubMed: 37827156
Improving the response to oxaliplatin by targeting chemotherapy-induced CLDN1 in resistant metastatic colorectal cancer cells [ Cell Biosci, 2023, 13(1):72] PubMed: 37041570
Systematic screening identifies ABCG2 as critical factor underlying synergy of kinase inhibitors with transcriptional CDK inhibitors [ Breast Cancer Res, 2023, 25(1):51] PubMed: 37147730
The p38/MK2 Pathway Functions as Chk1-Backup Downstream of ATM/ATR in G2-Checkpoint Activation in Cells Exposed to Ionizing Radiation [ Cells, 2023, 12(10)1387] PubMed: 37408221
A Chemical Proteomics Approach to Discover Regulators of Innate Immune Signaling [ Viruses, 2023, 15(5)1112] PubMed: 37243198
p38 Mitogen-Activated Protein Kinase Inhibition of Mesenchymal Transdifferentiated Tumor Cells in Head and Neck Squamous Cell Carcinoma [ Biomedicines, 2023, 11(12)3301] PubMed: 38137525
Integrative analysis of drug response and clinical outcome in acute myeloid leukemia [ Cancer Cell, 2022, S1535-6108(22)00312-9] PubMed: 35868306
MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells [ Cancer Cell, 2022, S1535-6108(21)00662-0] PubMed: 35051357
Proteogenomics refines the molecular classification of chronic lymphocytic leukemia [ Nat Commun, 2022, 13(1):6226] PubMed: 36266272

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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.

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