400-998-5282
专注多肽 服务科研
400-998-5282
专注多肽 服务科研
Tosedostat是一种新型且强效的口服氨基肽酶抑制剂，在先前针对老年复发或难治性急性髓系白血病（AML）患者的1-2期研究中已显示出临床活性。
编号：566752
CAS号：238750-77-1
单字母：
| 编号: | 566752 |
| 中文名称: | 托舍多特、Tosedostat |
| 英文名: | Tosedostat |
| CAS号: | 238750-77-1 |
| 三字母: | 238750-77-1 |
| 分子式: | C21H30N2O6 |
| 系统命名法: | cyclopentyl (2S)-2-[[(2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl]amino]-2-phenylacetate |
| 标签: | 氨肽酶(Aminopeptidase) |
| Canonical SMILES: | CC(C)CC(C(C(=O)NO)O)C(=O)NC(C1=CC=CC=C1)C(=O)OC2CCCC2 |
| 实验参考方法（Cell experiment）: | Cell lines：Human multiple myeloma (MM) cells. Preparation method：The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. Reacting condition：10 μM, 72 hours. Applications：CHR2797 showed antiproliferative and apoptotic effects against MM in vitro by inducing the AA deprivation response (AADR). Using MTS and CTG assays, CHR2797, at clinically achievable concentrations, decreased survival and proliferation in MM1S and IL-6-dependent ANBL6 cells, in the presence or absence of bone marrow stromal cells following 72 hours incubation. CHR2797 induced apoptosis in MM cells via activation of Caspase 3/7 and 9 but not Caspase 8. CHR2797 (10 μM) induced apoptosis in patient MM cells. Combined treatment with CHR2797 and LBH589 in MM cells (MM1S, ANBL6, and INA6) further reduced cell viability following 72 hour incubation when compared with CHR2797 treatment alone. CHR2797 (1 μM) in combination with LBH589 (1 nM) showed an increased growth arrest in G0/G1 cells in MM1R cells treated with both drugs versus CHR2797 alone after 24 hours. CHR2797 inhibited anti-apoptotic protein Mcl-1 in MM1R and U266 MM cells. |
| 溶解度: | ≥ 40.6 mg/mL in DMSO, ≥ 15.07 mg/mL in EtOH with ultrasonic |
Tosedostat是一种新型且强效的口服氨基肽酶抑制剂，在先前针对老年复发或难治性急性髓系白血病（AML）患者的1-2期研究中已显示出临床活性。 [2]
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]
氨基肽酶在蛋白质细胞周期中发挥着关键作用。抑制氨基肽酶会导致氨基酸剥夺反应，该反应选择性地发生在转化细胞中，并导致促凋亡因子（包括CHOP和NOXA）的上调、应激相关通路（如NFκB）的激活以及mTOR的抑制，从而关闭蛋白质合成。 [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（Tosedostat，CHR-2797）在细胞内转化为具有药理活性的代谢产物CHR-79888。 [1]
Tosedostat (CHR-2797) is converted intracellularly into a pharmacologically active metabolite CHR-79888. [1]
Tosedostat具有抗增殖、抗血管生成和促凋亡的作用。目前，Tosedostat正处于抗癌治疗的临床试验阶段，并显示出对包括光滑念珠菌在内的不同念珠菌属具有广泛的抗真菌活性。Tosedostat通过阻断蛋白质回收来耗竭敏感肿瘤细胞的氨基酸，从而产生抗增殖作用。Tosedostat对复发或难治性急性髓系白血病（AML）的老年患者有效。 [2]
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]
相关文献：
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.
氨基肽酶是一类广泛分布于细菌、真菌、动物和植物中的酶，它们通过水解多肽链N端附近的肽键，催化蛋白质或肽底物氨基末端的氨基酸裂解。大多数氨基肽酶由相对大分子量（50kDa）的亚基组装而成，呈现多聚体结构，而有些则是单聚体。大多数氨基肽酶是锌金属酶，因此会被过渡态类似物bestatin抑制。氨基肽酶存在于许多亚细胞器以及细胞质和膜中，它们参与多种蛋白水解途径，并在蛋白质成熟、非激素和激素肽的降解以及可能决定蛋白质稳定性方面发挥重要作用。
Aminopeptidases are a group of enzymes widely distributed among bacteria, fungi, animals and plants that catalyze the cleavage of amino acids from the amino terminus of protein or peptide substrates through hydrolysis of peptide bonds near the N-terminal end of a polypeptide chain. Most aminopeptidases are assembled by relatively high mass (50kDa) subunits exhibiting multimeric structures, whereas some are monomeric. The majority of aminopeptidases are zinc metalloenzymes and hence inhibited by the transition-state analog bestatin. Aminopeptidases have been found in many subcellular organelles as well as in cytoplasm and membrane, where they are involved in diverse proteolytic pathways and play an essential role in protein maturation, degradation of non-hormonal and hormonal peptides and possibly determination of protein stability.
