Ralimetinib-dimesylate-LY2228820-dimesylate-DataSheet-生命科學(xué)試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemERalimetinib dimesylateCat. No.: HY-13241CAS No.: 862507-23-1Synonyms: LY2228820 dimesylate分式: CHFNOS分量: 612.74作靶點: p38 MAPK作通路: MAPK/ERK Pathway儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO

2、 : 61 mg/mL (99.55 mM; Need ultrasonic and warming)Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 1.6320 mL 8.1601 mL 16.3201 mL5 mM 0.3264 mL 1.6320 mL 3.2640 mL10 mM 0.1632 mL 0.8160 mL 1.6320 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當(dāng)?shù)娜芙獍?，配制前請先配制澄清的儲備液，再依次添加助溶?為保證實驗結(jié)

3、果的可靠性，體內(nèi)實驗的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使；澄清的儲備液可以根據(jù)儲存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (4.08 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (4.08 mM); Clear solution3. 請依序添加每種溶劑： 10% DMSO 90% co

4、rn oil1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.5 mg/mL (4.08 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Ralimetinib dimesylate (LY2228820 dimesylate)種選擇性，ATP競爭性的 p38 MAPK / 抑制劑，IC50分別為5.3 和 3.2 nM。IC50 & Target p38 MAPK p38 MAPK3.2 nM (IC50) 5.3 nM (IC50)體外研究 Ralimetinib dimesyl

5、ate inhibits p38, as well as the level of phosphoMAPKAPK-2 (pMK2) in RAW 264.7cells, with IC50 values of 7 nM and 34.3 nM, respectively. Furthermore, Ralimetinib dimesylate inhibitslipopolysaccharide (LPS)-induced TNF formation in murine peritoneal macrophages, with IC50 of 5.2 nM1. In multiple myel

6、oma (MM) cells, including INA6, RPMI-8226, U266, and RPMI-Dox40, Ralimetinibdimesylate (LY2228820) (200 nM-800 nM) significantly blocks p38MAPK signaling, as revealed by itsinhibition on phosphorylation of HSP27, a downstream target of p38MAPK, without affecting the expressionlevel of HSP27. Ralimet

7、inib dimesylate (200 nM-400 nM) enhances bortezomib-induced cytotoxicity andapoptosis, but Ralimetinib dimesylate alone doesnt inhibit the growth of MM.1S cells. Ralimetinib dimesylate(200 nM-800 nM) also inhibits secretion of IL-6 and MIP-1 in long-term BM stromal cells (LT-BMSCs), BMmononuclear ce

8、lls (BMMNCs), peripheral blood (PB) CD138+, CD138- or PB CD14+ cells. Ralimetinibdimesylate (400 nM-800 nM) also blocks osteoclastogenesis from CD14+ cells 2.體內(nèi)研究 In LPS-induced mice, Ralimetinib dimesylate effectively inhibits the formation of TNF with a thresholdminimum 50% effective dose (TMED50)

9、 less than 1 mg/kg. In a rat model of collagen-inducedarthritis (CIA),Ralimetinib dimesylate displays potent effects on paw swelling, bone erosion, and cartilage destruction, witha threshold minimum 50% effective dose (TMED50)of 1.5 mg/kg 1. Ralimetinib dimesylate inhibits tumorphospho-MK2 in a dose

10、-dependent manner (TED50=1.95 mg/kg, TED70=11.17 mg/kg) in mice implantedwith B16-F10 melanoma. Ralimetinib dimesylate inhibits MK2 phosphorylation: mouse in vivo TED50=1.01mg/kg (compound exposure approximately 100 nM) and human ex vivo IC50=0.12 M with either mouse orhuman PBMC 3.PROTOCOLKinase As

11、say 1 Inhibition of p38 is determined using recombinant human p38 in a standard filter binding protocol usingATP-33P and EGFR 21-mer peptide as substrate. Functional inhibition of TNF in murine peritonealmacrophages is determined using LPS stimulation in the presence of Ralimetinib. To assess p38 ac

12、tivity incells more directly, RAW 264.7 cells are treated with Ralimetinib and then stimulated with anisomycin. Thelevel of p38 activity is detected using a phosphoMAPKAPK-2 (pMK2) (Thr 334) antibody which reacts with aresidue specifically phosphorylated by p38.MCE has not independently confirmed th

13、e accuracy of these methods. They are for reference only.Animal Murine B16-F10 melanoma cells are cultured in Dulbeccos Modified Eagle Medium supplemented with l-2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEAdministration 3 glutamine, high glucose and 10% FBS (GIBCO 11965-092). C57/bl6 mice are

14、implanted in the rear flank withB16-F10 cells (2106), and when tumors reach approximately 200 mm3 in size, are dosed orally withRalimetinib dimesylate in 1% carboxymethylcellulose/0.25% Tween 80. Two hours postdose, tumors areexcised, homogenized, and lysed for Western blot analysis. MK2 phosphoryla

15、tion (p-Thr334), normalized tototal glyceraldehyde-3-phosphate dehydrogenase, is quantified by chemiluminescent detection. The 50% or70% threshold effective dose (TED50 and TED70, respectively) is calculated to approximate effective doseranges for testing of Ralimetinib dimesylate in xenograft model

16、s, that is, where significant target inhibition isobserved. The TED50 or TED70 is defined as the dose where a statistically significant effect is achieved, andthere is at least 50% or 70% inhibition, respectively, compared with vehicle control.MCE has not independently confirmed the accuracy of thes

17、e methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻 Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. EBioMedicine. 2015 Nov 19;2(12):1944-56. Cell Biol Int. 2019 Jul 19. Mol Med Rep. 2019 May 22. Harvard Medical School LINCS LIBRARYSee more customer validations on HYPERLINK / www.MedChemEREFERENCE

18、S1. Mader M, et al. Imidazolyl benzimidazoles and imidazo4,5-bpyridines as potent p38alpha MAP kinase inhibitors with excellent in vivoantiinflammatory properties. Bioorg Med Chem Lett, 2008, 18(1), 179-183.2. Ishitsuka K, et al. p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibitsosteoclastogenesis in multiple myeloma; therapeutic implications. Br J Haematol, 2008, 141(5), 598-606.3. Campbell RM, et al. Characterization of LY2228820 dimesylate, a potent and selective i