S26163
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- 公司名稱 上海源葉生物科技有限公司
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- 更新時間 2024/7/2 19:50:42
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- 產(chǎn)品描述： CHR-2797 is an orally bioavailable inhibitor of the M1 family of aminopeptidases with potential antineoplastic activity. CHR-2797 is converted intracellularly into a poorly membrane-permeable active metabolite (CHR-79888) which inhibits the M1 family of aminopeptidases, particularly puromycin-sensitive aminopeptidase (PuSA), and leukotriene A4 (LTA4) hydrolase; inhibition of these aminopeptidases in tumor cells may result in amino acid deprivation, inhibition of protein synthesis due to a decrease in the intracellular free amino acid pool, an increase in the level of the proapoptotic protein Noxa, and cell death
- 靶點： AChR;Aminopeptidase
- 體外研究： In HL-60 cells, the treatmentwith Tosedostat (CHR-2797) results in an increase in the secretion of Stanniocalcin 2 (STC2) protein into the growth medium. After 2 h treatment with Tosedostat (60 nM), increases in SLC7A11 expression are detectable. The for by Tosedostat inhibits the proliferation of U-937 and HuT 78 cell lines (IC50s: 10 nM; >10 μM). Tosedostat treatment increases expression of amino acid deprivation response (AADR) genes in U-937 cells but not in HuT 78 cells. By 24 h with Tosedostat (0.01 μM) the mean MCA production is reduced to 77.8% of the untreated control cells; similarly the MCA production is reduced to 51.3% with 1 μM, 38.5% with 5 μM, and 35.3% with 10 μM Tosedostat.
- 體內(nèi)研究： In vivo in rodent cancer models, Tosedostat (CHR-2797) has anticancer activity, and a dose-response relationship has been shown in two models. The effect of Tosedostat is less apparent when the tumor burden is higher before therapy.
- 細胞實驗： Tosedostat (CHR-2797) is stored at -20°C as a 10 mM stock in dimethyl sulfoxide (DMSO), and diluted with RPMI culture medium prior to use. Leukemic cells are washed and suspended in phosphate buffered saline (PBS). 100 μL of cell suspension (1×105 cells/mL) is mixed with 100 μL of Tosedostat (CHR-2797) (0.01 to 10 μM) and 200 μM L-alanine 4-methyl-coumaryl-7-amide (ala-MCA) in a 96 well plate in duplicate. The aminopeptidase activity is measured by detecting the fluorescent 7-amino-4-methylcoumarin (MCA) liberated from the cleavage of ala-MCA by cellular aminopeptidases (excitation 355 nm, emission 460 nm).
- 動物實驗： A breeding colony of NOD/SCID IL2R gammanull mice are used in this study. The mice are inoculated subcutaneously in the right flank with 2×106 H929 myeloma cells in 50 μL RPMI-1640 and 50 μL MatrigelTM Basement Membrane Matrix Growth Factor Reduced. The mice are assigned into the following four treatment groups (10 animals per group): no treatment, Tosedostat 75 mg/kg, CHR-3996 30 mg/kg, and Tosedostat 75 mg/kg with concomitant CHR-3996 30 mg/kg. Tosedostat is administered daily by intra-peritoneal injection beginning four days after the tumour cells are inoculated. Caliper measurements of the longest perpendicular tumour diameters (length) and width are performed every other day to estimate the tumour volume.
- 參考文獻：
1. Smith EM, et al.The combination of HDAC and aminopeptidase inhibitors is highly synergistic in myeloma and leads to disruption of the NFκB signalling pathway.Oncotarget. 2015 Jul 10;6(19):17314-27. 2. Krige D,etal.CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells.Cancer Res. 2008 Aug 15;68(16):6669-79. 3. Jenkins C, et al. Leuk Res. 2011 May;35(5):677-81. 4. van Herpen CM, et al. Br J Cancer. 2010 Oct 26;103(9):1362-8.
- 溶解度： Soluble in DMSO
- 保存條件： -20℃
- 配置溶液濃度參考：
1mg 5mg 10mg 1 mM 2.46 ml 12.301 ml 24.602 ml 5 mM 0.492 ml 2.46 ml 4.92 ml 10 mM 0.246 ml 1.23 ml 2.46 ml 50 mM 0.049 ml 0.246 ml 0.492 ml
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