1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemERuxolitinibCat. No.: HY-50856CAS No.: 941678-49-5Synonyms: INCB018424分式: CHN分量: 306.37作靶點: JAK; Autophagy; Mitophagy作通路: Epigenetics; JAK/STAT Signaling; Stem Cell/Wnt; Autophagy儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C

2、6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO : 36 mg/mL (117.50 mM)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.67 mg/mL (8.71 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.67 mg/mL (8.71 mM); Clear solution3. 請依序添加每種

3、溶劑： 10% DMSO 90% corn oilSolubility: 2.67 mg/mL (8.71 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Ruxolitinib是有效，選擇性的 JAK1/2 抑制劑， IC50 值分別為 3.3 nM和2.8 nM，選擇性是JAK3 的 130 多倍。IC50 & Target JAK2 JAK1 Tyk2 JAK32.8 nM (IC50) 3.3 nM (IC50) 19 nM (IC50) 428 nM (IC50)體外研究 Ruxolitinib potently and selectively i

4、nhibits JAK2V617F-mediated signaling and proliferation, markedlyincreases apoptosis in a dose dependent manner, and at 64 nM results in a doubling of cells with depolarizedmitochondria in Ba/F3 cells. Ruxolitinib demonstrates remarkable potency against erythroid colony formationwith IC50 of 67 nM, a

5、nd inhibits proliferating of erythroid progenitors from normal donors and polycythemiavera patients with IC50 values of 407 nM and 223 nM, respectively 1.體內(nèi)研究 Ruxolitinib (180 mg/kg, orally, twice a day) results in survive rate of greater than 90% by day 22 andmarkedly reduces splenomegaly and circu

6、lating levels of inflammatory cytokines, and preferentiallyeliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive orimmunosuppressive effects in a JAK2V617F-driven mouse model 1. In the Ruxolitinib group, the primaryend point is reached in 41.9% of patien

7、ts, as compared with 0.7% in the placebo group in the double-blindtrial of myelofibrosis. Ruxolitinib results in maintaining of reduction in spleen volume and improvement of50% or more in the total symptom score 2. Ruxolitinib (15 mg twice daily) treatment leads a total of 28% ofthe patients to have

8、 at least a 35% reduction in spleen volume at week 48 in patients with myelofibrosis, ascompared with 0% in the group receiving the best available therapy. The mean palpable spleen length hasdecreased by 56% with Ruxolitinib but has increased by 4% with the best available therapy at week 48.Patients

9、 in the ruxolitinib group has an improvement in overall quality-of-life measures and a reduction insymptoms associated with myelofibrosis 3.PROTOCOLKinase Assay 1 Recombinant proteins are expressed using Sf21 cells and baculovirus vectors and purified with affinitychromatography. JAK kinase assays u

10、se a homogeneous time-resolved fluorescence assay with the peptidesubstrate (-EQEDEPEGDYFEWLE). Each enzyme reaction is carried out with Ruxolitinib or control, JAKenzyme, 500 nM peptide, adenosine triphosphate (ATP; 1mM), and 2% dimethyl sulfoxide (DMSO) for 1hour. The 50% inhibitory concentration

11、(IC50) is calculated as INCB018424 concentration required forinhibition of 50% of the fluorescent signal.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 1 Cells are seeded at 2103/well of white bottom 96-well plates, treated with Ruxolitinib

12、(INCB018424) from2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEDMSO stocks (0.2% final DMSO concentration), and incubated for 48 hours at 37C with 5% CO2. Viability ismeasured by cellular ATP determination using the Cell-Titer Glo luciferase reagent or viable cell counting.Values are transformed

13、to percent inhibition relative to vehicle control, and IC50 curves are fitted accordingto nonlinear regression analysis of the data using PRISM GraphPad.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice are fed standard rodent chow and provide

14、d with water ad libitum. Ba/F3-JAK2V617F cells (105 perAdministration 1 mouse) are inoculated intravenously into 6- to 8-week-old female BALB/c mice. Survival is monitored daily,and moribund mice are humanely killed and considered deceased at time of death. Treatment with vehicle(5% dimethyl acetami

15、de, 0.5% methocellulose) or Ruxolitinib (INCB018424) begin within 24 hours of cellinoculation, twice daily by oral gavage. Hematologic parameters are measured using a Bayer Advia120analyzed, and statistical significance is determined using Dunnett testing.MCE has not independently confirmed the accu

16、racy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻 Nat Med. 2018 Aug;24(8):1143-1150. Cancer Discov. 2018 May;8(5):616-631. Gut. 2019 May 10. pii: gutjnl-2018-317424. Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. Blood. 2014 Dec 18;124(26):3924-31.See more customer validations on H

17、YPERLINK / www.MedChemEREFERENCES1. Quintas-Cardama A, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for thetreatment of myeloproliferative neoplasms. Blood, 2010, 115(15), 3109-3117.2. Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med, 2012, 366(9), 799-807.3. Harrison C, et al. JAK inhibition with ruxolitinib versus best available th