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Tosedostat (CHR2797)

现货
Catalog No.
A4355
氨肽酶(Aminopeptidase)抑制剂
组合的产品项目
规格价格库存 数量
1mg
¥ 1,680.00
现货
10mg
¥ 3,580.00
现货

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Background

Tosedostat is a novel and potent oral aminopeptidase inhibitor with clinical activity in a previous phase 1–2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). [2]
Aminopeptidases play a key role in the protein cell cycle. Inhibition of aminopeptidase results in the amino acid deprivation response, which occurs selectively in transformed cells and leads to upregulation of proapoptotic factors including CHOP and NOXA, activation of stress-related pathways such as NFκB, and inhibition of mTOR, which switches off protein synthesis. [2]
Tosedostat (CHR-2797) is converted intracellularly into a pharmacologically active metabolite CHR-79888. [1]
Tosedostat has antiproliferative, antiangiogenic and proapoptotic effects. Tosedostat is currently in a clinical trial phase for anticancer therapy, and displayed a broad antifungal activity against different Candida spp, including Candida glabrata. Tosedostat depletes sensitive tumour cells of amino acids by blocking protein recycling and thereby generates an antiproliferative effect. Tosedostat has activity in older patients with relapsed or refractory AML. [2]
References:
1.Van Herpen CM, Eskens FA, de Jonge M et al. A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours. Br J Cancer. 2010 Oct 26;103(9):1362-8.
2.Cortes J, Feldman E, Yee K et al. Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study. Lancet Oncol. 2013 Apr;14(4):354-62.

文献引用

1.Drinkwater, Nyssa, et al. "X‐ray crystal structures of an orally available aminopeptidase inhibitor, Tosedostat, bound to anti‐malarial drug targets PfA‐M1 and PfA‐M17." Proteins: Structure, Function, and Bioinformatics (2015). PMID:25645579

Chemical Properties

StorageStore at -20°C
M.Wt406.47
Cas No.238750-77-1
FormulaC21H30N2O6
Solubility≥40.6 mg/mL in DMSO, ≥15.07 mg/mL in EtOH with ultrasonic, <2.53 mg/mL in H2O
Chemical Namecyclopentyl (2S)-2-[[(2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl]amino]-2-phenylacetate
SDFDownload SDF
Canonical SMILESCC(C)CC(C(C(=O)NO)O)C(=O)NC(C1=CC=CC=C1)C(=O)OC2CCCC2
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验 [1]:

细胞系

人多发性骨髓瘤(MM)细胞

溶解方法

该化合物在DMSO中的溶解度大于10 mM。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

10 μM,72小时

应用

CHR2797在体外通过诱导AA剥夺反应(AADR)发挥抗MM的抗增殖和凋亡作用。在临床可实现的浓度下,使用MTS和CTG测定法检测,在存在或不存在骨髓基质细胞条件下,CHR2797孵育72小时后,降低MM1S和IL-6依赖性ANBL6细胞的存活和增殖。CHR2797通过激活Caspase 3/7和9诱导MM细胞凋亡,不作用于Caspase 8。CHR2797(10 μM)诱导患者MM细胞凋亡。在MM细胞(MM1S、ANBL6和INA6)中,与单独的CHR2797治疗相比,CHR2797孵育72小时后,CHR2797和LBH589的联合治疗进一步降低了细胞活力。在MM1R细胞中,与单独使用CHR2797相比,给药24小时后,CHR2797(1 μM)与LBH589(1 nM)联合给药造成G0/G1细胞生长停滞增加。CHR2797抑制MM1R和U266 MM细胞中的抗凋亡蛋白Mcl-1。

临床试验 [2]:

患者

急性骨髓性白血病和骨髓增生异常患者

给药剂量

60-180 mg,28天,胶囊,每日饭后口服

应用

口服每日一次给药130 mg tosedostat表现出良好的耐受性,具有显著的抗白血病活性。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Acharya C, Zhong M Y, Tannenbaum D, et al. Targeting Aminopeptidases by Tosedostat (TST)(CHR2797), Alone and with LBH589, Induces Significant Cytotoxicity Against Human Multiple Myeloma (MM) Cells[J]. 2012.

[2]. Lwenberg B, Morgan G, Ossenkoppele G J, et al. Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia[J]. Journal of Clinical Oncology, 2010, 28(28): 4333-4338.

生物活性

描述 Tosedostat是LAP、PuSA 和Aminopeptidase N的抑制剂,IC50值分别为100 nM、150 nM和220 nM。
靶点 LAP PuSA Aminopeptidase N      
IC50 100 nM 150 nM 220 nM      

质量控制

化学结构

Tosedostat (CHR2797)

相关生物数据

Gap 26