Pomalidomide-CC-4047-DataSheet-生命科學試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEPomalidomideCat. No.: HY-10984CAS No.: 19171-19-8Synonyms: CC-4047分式: CHNO分量: 273.24作靶點: Ligand for E3 Ligase作通路: PROTAC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 : 100 mg/mL (365.98 mM)

2、* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 3.6598 mL 18.2989 mL 36.5979 mL5 mM 0.7320 mL 3.6598 mL 7.3196 mL10 mM 0.3660 mL 1.8299 mL 3.6598 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?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)果的可靠性，體內(nèi)實

3、驗的作液，建議您現(xiàn)現(xiàn)配，當天使；澄清的儲備液可以根據(jù)儲存條件，適當保存；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 (9.15 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (9.15 mM); Clear solution1/4 Master of Small Molecules 您邊的抑制劑師www.MedChemEBIO

4、LOGICAL ACTIVITY物活性 Pomalidomide第三代免疫調(diào)節(jié)劑，與 E3 連接酶 cereblon 相互作，誘導必需的 Ikaros 轉(zhuǎn)錄因的降解。IC50 & Target Cereblon體外研究 Pomalidomide also inhibits Whole Blood TNF- with IC50 of 25 nM 1. Exposure of lymphoma cells toPomalidomide (CC-4047) leads to 40% decrease in cell proliferation when compared with vehicle-t

5、reatedcontrols. Pomalidomide inhibits by 40% the DNA synthesis of Raji cells (P=0.036) 2. In both CD4+ andCD8+ cells, Pomalidomide (CC-4047) is the most potent IL-2-elevator, followed by CC-6032 and CC-5013.Pomalidomide is significantly more potent than CC-5013 at elevating IL-2, IL-5, and IL-10, an

6、d slightly morepotent than CC-5013 at elevating IFN- 3.體內(nèi)研究 The administration of Pomalidomide (CC-4047) for two consecutive days before mAb therapy enhances theantitumor activity of Rituximab and doubled the median survival of lymphoma-bearing mice. Statistically,significant differences are observe

7、d between animals treated with Rituximab versusPomalidomide+Rituximab. The median survival time of animals treated with Pomalidomide and Rituximab islonger (median survival, 74 days; 95% CI, 70-78) than those treated with Rituximab monotherapy (mediansurvival, 38 days; 95% CI, 26-50; log-rank test,

8、P=0.002). The administration of CC-5013 or Pomalidomidefor two consecutive days leads to a significant increase in the number of circulating NK cells as shown byflow cytometry analysis, in lymphoma-bearing SCID mice 2. Following a 50 mg/kg PO administration ofPomalidomide (POM) to rats, unbound conc

9、entrations in blood reach a Cmax value of 110082 ng/mL at4.62.4 hours, with a concomitant AUC(0-10) value of 68002000 nghr/mL. Unbound POM in the brain,however, has a Cmax value of 43063 ng/mL at 4.11.5 hours and an AUC(0-10) value of 2700740nghr/mL, giving an unbound AUCbrain to AUCblood ratio of 0

10、.390.03. These values are consistent withexcellent blood-brain-barrier penetration. The results obtained in this study are consistent with those seen ina concurrent study looking at whole brain POM content following its oral administration to mice 4.PROTOCOLCell Assay 2 Lymphoma cell lines are place

11、d in 96-well plates (1105 cells per well) and exposed to escalatingconcentrations of CC-5013, Pomalidomide (2.5, 5, 10, 20, and 40 g/mL), or vehicle control single agents orin combination with Rituximab or Trastuzumab (isotype), at a final antibody concentration of 10 g/mL. Thefinal concentration is

12、 adjusted to 200 L with 10% RPMI. The cell lines are incubated at 37C and 5% CO2for 24 and 48 hours. Following 24 or 48 hours, 1 Ci per well of 3H-thymidine is added and cells areincubated for 18 hours more. Cells are then harvested using the Harvest system into the 96-well glass filtersand 3H-thymi

13、dine uptake is measured using an automated scintillation counter. Each experiment is done intriplicate at three different times; results are presented as the mean of counts per minute (cpm) at 24 and 48hoursSD 2.MCE has not independently confirmed the accuracy of these methods. They are for referenc

14、e only.Animal Mice 22/4 Master of Small Molecules 您邊的抑制劑師www.MedChemEAdministration 24 Six- to 8-week-old SCID mice are used for this purpose. On day 0, all the animals receive 1106 Raji cellsvia tail vein injection. After 72 hours of tumor engraftment, the animals are divided into seven cohorts. Th

15、efirst cohort (group A) serve as control and receive no treatment. Groups B and C consist of animals treatedwith either CC-5013 (0.5 mg/kg) or Pomalidomide (0.5 mg/kg) given i.p. on days +3, +4, +8, +9, +13, +14,+18, and +19. Groups D and E are treated with Rituximab or Trastuzumab (isotype control)

16、 monotherapygiven via tail vein injection at 10 mg/kg on days +5, +10, +15, and +20. Finally, groups F and G consist ofanimals treated with Rituximab in combination with CC-5013 (group E) or Pomalidomide (group G). IMiDs aregiven i.p. for two consecutive days before each dose of Rituximab. After com

17、pletion of therapy, animals areobserved for a period of 90 days. The end point of the study is survival defined as the time for thedevelopment of limb paralysis. Animals that reach the end point or survived after 3 months of observation aresacrificed by cervical dislocation. Pathologic examination o

18、f all organs (liver, lung, and brain) is done todetect any residual disease. The experiments are repeated in three separate occasions.Rats 4A total of 3 male CD-IGS rats are used. Pomalidomide is administered as a single PO administration via thestomach cannula, at 50 mg/kg (5 mL/kg) in a 0.5% carbo

19、xymethylcellulose/0.25% Tween 80 suspensionformulation. Microdialysate is collected in a cooling fraction collector, set at 4C at intervals of 25 minutes for10 hours after dosing. To calculate AUC, the corrected concentration of each sample is multiplied by theinterval over which the sample is colle

20、cted; in this case 25 minutes, and divided by 60 minutes per hour. Thesum of these values represented the total AUC value over the specified time range. To generate graphs, theconcentration at each time point is plotted at the mid-point of each collection interval. Microdialysates arecollected at th

21、e specified time points and analyzed for Pomalidomide concentration using a LC-MS/MSassay, within 12 hours.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻 Nat Commun. 2017 May 22;8:15398. Elife. 2018 Aug 1;7. pii: e38430. Gen Comp Endocrinol

22、. 2015 Dec 30;228:1-8. Faculty of Science, Masaryk University. Department of Experimental Biology.2014.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Zhu YX, et al. Molecular mechanism of action of the immune-modulatory drugs, thalidomide, lenalidomide and pomalidomide in mult

23、iplemyeloma. Leuk Lymphoma. 2013 Apr;54(4):683-7.2. Hernandez-Ilizaliturri FJ1, et al. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severecombined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005 Aug 15;11(16):5984-92.3. Schafer PH, et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-relatedimmunomodulatory drugs. J Pharmacol Exp Ther. 2003 Ju