Home MAPK p38 MAPK inhibitor Ralimetinib (LY2228820) dimesylate For research use only.

Ralimetinib (LY2228820) dimesylate

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.

Ralimetinib (LY2228820) dimesylate Chemical Structure

Ralimetinib (LY2228820) dimesylate Chemical Structure

CAS No. 862507-23-1

Purity & Quality Control

Ralimetinib (LY2228820) dimesylate Related Products

Signaling Pathway

p38 MAPK Signaling Pathways

p38 MAPK Signaling Pathway

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
RPMI-8226 Kinase assay ~800 nM DMSO inhibits phosphorylation of HSP27 18397345
U266 Kinase assay ~800 nM DMSO inhibits phosphorylation of HSP27 18397345
MM.1S Kinase assay ~800 nM DMSO inhibits phosphorylation of HSP27 18397345
RPMI-Dox40 Kinase assay ~800 nM DMSO inhibits phosphorylation of HSP27 18397345
RPMI-LR5 Kinase assay ~800 nM DMSO inhibits phosphorylation of HSP27 18397345
INA-6 Kinase assay ~800 nM DMSO inhibits phosphorylation of HSP27 18397345
RPMI-8226 Cytoxicity assay ~1000 nM DMSO no significant cytotoxicity 18397345
U266 Cytoxicity assay ~1000 nM DMSO no significant cytotoxicity 18397345
MM.1S Cytoxicity assay ~1000 nM DMSO no significant cytotoxicity 18397345
RPMI-Dox40 Cytoxicity assay ~1000 nM DMSO no significant cytotoxicity 18397345
RPMI-LR5 Cytoxicity assay ~1000 nM DMSO no significant cytotoxicity 18397345
INA-6 Cytoxicity assay ~1000 nM DMSO no significant cytotoxicity 18397345
CD14+ Function assay ~800 nM DMSO inhibits osteoclastogenesis from CD14 positive cells 18397345
U-87-MG Function assay 1 μM DMSO reduces tumor-driven cord formation 23335506
MDA-MB-231 Function assay 1 μM DMSO reduces tumor-driven cord formation 23335506
A-2780 Function assay 1 μM DMSO reduces tumor-driven cord formation 23335506
SK-OV-3 Function assay 1 μM DMSO reduces tumor-driven cord formation 23335506
LXFA-629 Function assay 1 μM DMSO reduces tumor-driven cord formation 23335506
NCI-H1650 Function assay 1 μM DMSO reduces tumor-driven cord formation 23335506
PC-3 Function assay 1 μM DMSO reduces tumor-driven cord formation 23335506
RAW264.7 Function assay ~20 μM DMSO inhibits Anisomycin-stimulated MK2 phosphorylation with IC50 of 35.3 nM 24356814
mouse peritoneal macrophages Function assay ~20 μM DMSO LPS/IFN-γ–stimulated TNF-α production with IC50 of 6.3 nM 24356814
A549 Function assay ~20 μM DMSO inhibits LPS-induced CXCL8 production with IC50 of 144.9 nM 24356814
MDA-231 Function assay ~10 μM suppresses DKK-1 expression 26407843
MCF-7 Function assay ~10 μM suppresses DKK-1 expression 26407843
MDA-435 Function assay ~10 μM suppresses DKK-1 expression 26407843
PC3 Function assay ~10 μM DMSO suppresses DKK-1 expression 26913608
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells 29435139
DAOY qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells 29435139
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells 29435139
RD qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells 29435139
Rh30 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh30 cells 29435139
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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
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 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]
Kinase Assay 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 Research 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.
Experimental Result Images Methods Biomarkers Images PMID
Western blot p-p38 / p38α / p38β / p-MK2 / MK2 / p-HSP27 / HSP27 p-S6K 23335506
In Vivo
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]
Animal Research Animal Models Lipopolysaccharide (LPS)-induced Balb/c mice
Dosages 0–20 mg/kg
Administration Oral bid dosing for 14 days
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02860780 Completed
Advanced Cancer|Metastatic Cancer|Colorectal Cancer|Non-small Cell Lung Cancer
Eli Lilly and Company
 August 10 2016 Phase 1
NCT02364206 Completed
Adult Glioblastoma
Centre Jean Perrin|National Cancer Institute France|ARC Foundation for Cancer Research
 June 8 2015 Phase 1|Phase 2
NCT02322853 Terminated
Postmenopausal|Metastatic Breast Cancer
Centre Francois Baclesse|National Cancer Institute France|ARC Foundation for Cancer Research
 January 2015 Phase 2
NCT01393990 Completed
Advanced Cancer
Eli Lilly and Company
 September 4 2008 Phase 1

Chemical Information & Solubility

Molecular Weight 612.74 Formula

C24H29FN6.2CH4O3S
CAS No. 862507-23-1 SDF Download Ralimetinib (LY2228820) dimesylate SDF
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
Storage (From the date of receipt)

In vitro
Batch:

Water : 123 mg/mL

DMSO : 35 mg/mL ( (57.12 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 3 mg/mL


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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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