Ralimetinib (LY2228820)

Catalog No.S1494

Ralimetinib (LY2228820) Chemical Structure

Molecular Weight(MW): 612.74

Ralimetinib (LY2228820) 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.

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Cited by 20 Publications

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Biological Activity

Description Ralimetinib (LY2228820) 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]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
RPMI-8226 MWrLbY5ie2ViYYPzZZk> Mlu4glgxOCCwTR?= NV2wV2tjTE2VTx?= NFfkOopqdmirYnn0d{BxcG:|cHjvdplt[XSrb36gc4YhUFOSMke= MXGxPFM6PzN2NR?=
U266 MoTmT4lv[XOnIHHzd4F6 M4HCPJ45ODBibl2= NEfMd3FFVVOR M2Xh[YlvcGmkaYTzJJBpd3OyaH;yfYxifGmxbjDv[kBJW1B{Nx?= NHnG[4QyQDN7N{O0OS=>
MM.1S MUPLbY5ie2ViYYPzZZk> M2OzeZ45ODBibl2= M1[we2ROW09? MYrpcohq[mm2czDwbI9{eGixconsZZRqd25ib3[gTHNROjd? NEXJXZoyQDN7N{O0OS=>
RPMI-Dox40 NG[yOGVMcW6jc3WgZZN{[Xl? M3XufZ45ODBibl2= MnLiSG1UVw>? MnXCbY5pcWKrdIOgdIhwe3Cqb4L5cIF1cW:wIH;mJGhUWDJ5 NGHQeFYyQDN7N{O0OS=>
RPMI-LR5 MmC2T4lv[XOnIHHzd4F6 NWfMN2tFhjhyMDDuUS=> Mn;HSG1UVw>? MoO0bY5pcWKrdIOgdIhwe3Cqb4L5cIF1cW:wIH;mJGhUWDJ5 M4fqbFE5Ozl5M{S1
INA-6 M1HNdGtqdmG|ZTDhd5NigQ>? M2XvO545ODBibl2= M4HUO2ROW09? NHy2TldqdmirYnn0d{BxcG:|cHjvdplt[XSrb36gc4YhUFOSMke= M3X1[lE5Ozl5M{S1
RPMI-8226 NGG0bGxEgXSxeHnjbZR6KGG|c3H5 NW[5fI1mhjFyMECgcm0> Mo\WSG1UVw>? NYe2bpFodm9ic3nncolncWOjboSgZ5l1d3SxeHnjbZR6 M2exUVE5Ozl5M{S1
U266 MXfDfZRwgGmlaYT5JIF{e2G7 M2D4Sp4yODByIH7N NVrzd3N1TE2VTx?= M{X0TY5wKHOrZ37p[olk[W62IHP5eI91d3irY3n0fS=> NXnmW3JmOTh|OUezOFU>
MM.1S MkKxR5l1d3irY3n0fUBie3OjeR?= NXG5WGJshjFyMECgcm0> NGH2XYlFVVOR M3nkbo5wKHOrZ37p[olk[W62IHP5eI91d3irY3n0fS=> NFLq[ZkyQDN7N{O0OS=>
RPMI-Dox40 MoLUR5l1d3irY3n0fUBie3OjeR?= MorLglExODBibl2= MlrySG1UVw>? MYLuc{B{cWewaX\pZ4FvfCCleYTveI95cWOrdIm= MXOxPFM6PzN2NR?=
RPMI-LR5 NVyxV2xuS3m2b4jpZ4l1gSCjc4PhfS=> MVv+NVAxOCCwTR?= NFrSc41FVVOR MnXPco8he2mpbnnmbYNidnRiY4n0c5RwgGmlaYT5 MlSwNVg{QTd|NEW=
INA-6 MX;DfZRwgGmlaYT5JIF{e2G7 Mm\aglExODBibl2= MlXSSG1UVw>? MUXuc{B{cWewaX\pZ4FvfCCleYTveI95cWOrdIm= MlPqNVg{QTd|NEW=
CD14+ MkHYSpVv[3Srb36gZZN{[Xl? NFq5UnV,QDByIH7N MmDzSG1UVw>? NWrLRVRScW6qaXLpeJMhd3O2ZX;jcIF{fG:pZX7ld4l{KG[{b32gR2QyPCCyb4PpeIl3\SClZXzsdy=> M1TodFE5Ozl5M{S1
U-87-MG MUXGeY5kfGmxbjDhd5NigQ>? MY[xJO69VQ>? NHPIeolFVVOR NWHyZXlYemWmdXPld{B1fW2xcj3kdol3\W5iY3;y[EBnd3KvYYTpc44> MUWyN|M{PTVyNh?=
MDA-MB-231 MoO4SpVv[3Srb36gZZN{[Xl? MUCxJO69VQ>? Mlf2SG1UVw>? MlvtdoVlfWOnczD0eY1wei2mcnn2[Y4h[2:{ZDDmc5Ju[XSrb36= NHTud4YzOzN|NUWwOi=>
A-2780 M4LpemZ2dmO2aX;uJIF{e2G7 MUWxJO69VQ>? MXHEUXNQ M1Llc5Jm\HWlZYOgeJVud3JvZILpeoVvKGOxcnSg[o9zdWG2aX;u MkfhNlM{OzV3ME[=
SK-OV-3 M{jHcmZ2dmO2aX;uJIF{e2G7 NULUO3ZkOSEQvF2= NVP4[HJ3TE2VTx?= M{WwdJJm\HWlZYOgeJVud3JvZILpeoVvKGOxcnSg[o9zdWG2aX;u MVyyN|M{PTVyNh?=
LXFA-629 M{TCTGZ2dmO2aX;uJIF{e2G7 MkDFNUDPxE1? MYjEUXNQ NVLMfYY5emWmdXPld{B1fW2xcj3kdol3\W5iY3;y[EBnd3KvYYTpc44> MmXnNlM{OzV3ME[=
NCI-H1650 NI\XTlZHfW6ldHnvckBie3OjeR?= NWrNNop2OSEQvF2= MYHEUXNQ NXzNS3N6emWmdXPld{B1fW2xcj3kdol3\W5iY3;y[EBnd3KvYYTpc44> M4LC[lI{OzN3NUC2
PC-3 M1LIVWZ2dmO2aX;uJIF{e2G7 NVrxe2ZjOSEQvF2= NETuZopFVVOR M{C3TJJm\HWlZYOgeJVud3JvZILpeoVvKGOxcnSg[o9zdWG2aX;u MYmyN|M{PTVyNh?=
RAW264.7 NGWwPYdHfW6ldHnvckBie3OjeR?= M1ixO54zOCEQvF2= NH7KbplFVVOR MlnFbY5pcWKrdIOgRY5qe2:veXPpck1{fGmvdXzheIVlKE2NMjDwbI9{eGixconsZZRqd25id3n0bEBKSzVyIH;mJFM2NjNibl2= MVOyOFM2PjhzNB?=
mouse peritoneal macrophages Ml3YSpVv[3Srb36gZZN{[Xl? MVH+NlAh|ryP NFT0V4NFVVOR NXfybo1xVFCVL1nGUk3Pu+LCk4P0bY12dGG2ZXSgWG5HNc7zIIDyc4R2[3Srb36ge4l1cCCLQ{WwJI9nKDZwMzDuUS=> MXGyOFM2PjhzNB?=
A549 NVz1VVlkTnWwY4Tpc44h[XO|YYm= M3vrN54zOCEQvF2= M{PaSGROW09? MYrpcohq[mm2czDMVHMucW6mdXPl[EBEYEOOODDwdo9lfWO2aX;uJJdqfGhiSVO1NEBw\iBzNESuPUBvVQ>? MV2yOFM2PjhzNB?=
MDA-231 NInEe2tHfW6ldHnvckBie3OjeR?= M{nHd54yOCEQvF2= M{LQXZN2eHC{ZYPz[ZMhTEuNLUGg[ZhxemW|c3nvci=> NVPVe|VDOjZ2MEe4OFM>
MCF-7 NUjsWZpFTnWwY4Tpc44h[XO|YYm= NH\5cGR,OTBizszN NIrQTox{fXCycnXzd4V{KESNSz2xJIV5eHKnc4Ppc44> MUeyOlQxPzh2Mx?=
MDA-435 MnPTSpVv[3Srb36gZZN{[Xl? M3zZVZ4yOCEQvF2= NHTqTHZ{fXCycnXzd4V{KESNSz2xJIV5eHKnc4Ppc44> Mki3NlY1ODd6NEO=
PC3 M{W1UWZ2dmO2aX;uJIF{e2G7 NIHCTIp,OTBizszN M{XETWROW09? M3jndJN2eHC{ZYPz[ZMhTEuNLUGg[ZhxemW|c3nvci=> NXHzdXNIOjZ7MUO2NFg>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-p38 / p38α / p38β / p-MK2 / MK2 / p-HSP27 / HSP27; 

PubMed: 23335506     


whole cell protein extracts were isolated from ECFCs or ADSCs following pretreatment with DMSO (−) or 1 μm LY2228820 dimesylate (+) for 30 min prior to the addition of 10 ng/ml VEGF, bFGF, EGF, or 100 ng/ml IL-6, and then the extracts were subjected to Western blot analysis using antisera directed against p-p38, p38α, p38β, p-MK2, total MK2, p-HSP27, total HSP27, and β-actin as a loading control.

p-S6K ; 

PubMed: 26844273     


CRC cells were treated with 4 μM LY2228820, 10 μM BIRB796 or 10 μM SB202190 for 2 h and p38 and mTORC1 signaling was analyzed by immunoblot.

23335506 26844273
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

Kinase Assay:[1]
+ Expand

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:[2, 3]
+ Expand
  • 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.
    (Only for Reference)
Animal Research:[1]
+ Expand
  • Animal Models: Lipopolysaccharide (LPS)-induced Balb/c mice
  • Formulation: Dissolved in 1% CMC/0.25% Tween 80 in water
  • Dosages: 0–20 mg/kg
  • Administration: Oral bid dosing for 14 days
    (Only for Reference)

Solubility (25°C)

In vitro Water 100 mg/mL warmed (163.2 mM)
DMSO 4 mg/mL warmed (6.52 mM)
Ethanol 3 mg/mL (4.89 mM)
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
Saline
For best results, use promptly after mixing.
30 mg/mL

* 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.

Chemical Information

Molecular Weight 612.74
Formula

C24H29FN6.2CH4O3S

CAS No. 862507-23-1
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02364206 Active not recruiting Adult Glioblastoma Centre Jean Perrin|National Cancer Institute France|ARC Foundation for Cancer Research June 8 2015 Phase 1|Phase 2
NCT02364206 Active not recruiting 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
NCT02322853 Terminated Postmenopausal|Metastatic Breast Cancer Centre Francois Baclesse|National Cancer Institute France|ARC Foundation for Cancer Research January 2015 Phase 2
NCT01663857 Completed Epithelial Ovarian Cancer|Fallopian Tube Cancer|Primary Peritoneal Cancer Eli Lilly and Company July 2012 Phase 1|Phase 2
NCT01663857 Completed Epithelial Ovarian Cancer|Fallopian Tube Cancer|Primary Peritoneal Cancer Eli Lilly and Company July 2012 Phase 1|Phase 2

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID