Ralimetinib-dimesylate-LY2228820-dimesylate-DataSheet-生命科学试剂-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作靶点: p38 MAPK作通路: MAPK/ERK Pathway储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO

2、 : 61 mg/mL (99.55 mM; Need ultrasonic and warming)Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液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请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂(为保证实验结

3、果的可靠性，体内实验的作液，建议您现现配，当天使；澄清的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (4.08 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (4.08 mM); Clear solution3. 请依序添加每种溶剂： 10% DMSO 90% co

4、rn oil1/3 Master of Small Molecules 您边的抑制剂师www.MedChemESolubility: 2.5 mg/mL (4.08 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Ralimetinib dimesylate (LY2228820 dimesylate)种选择性，ATP竞争性的 p38 MAPK / 抑制剂，IC50分别为5.3 和 3.2 nM。IC50 & Target p38 MAPK p38 MAPK3.2 nM (IC50) 5.3 nM (IC50)体外研究 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.体内研究 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 您边的抑制剂师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.户使本产品发表的科研献 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