AbMole Carfilzomib (PR-171)是一种不可逆的蛋白酶体 (proteasome) 抑制剂，IC50为<5 nM，在体外优先抑制β5亚基的ChT-L活性，对PGPH和T-L活性很弱或没有作用。
Carfilzomib (PR-171)在体外优先抑制β5亚基的ChT-L活性，对PGPH和T-L活性很弱或没有作用。Carfilzomib抑制多种细胞系的肿瘤细胞的增殖。Carfilzomib诱导内在和外在的凋亡信号传导途径并激活c-Jun N-末端激酶(JNK)。与bortezomib相比，Carfilzomib协同地塞米松(Dex)表现增强的抗MM活性。
Carfilzomib 降低 ANBL-6、RPMI 8226 细胞、U266 和 KAS-6/1 细胞的活力，IC50 小于 5 nM。Carfilzomib 克服了 Dex 耐药性，因为 MM1.R 细胞的 IC50 为 15.2 nM，低于亲本 MM1.S 细胞的 29.3 nM 值。与 carfilzomib 和 HDACI 共同处理导致在各种套细胞淋巴瘤细胞系和原代套细胞淋巴瘤细胞中协同诱导细胞死亡。在 HF-4B 和 Granta 细胞中，Carfilzomib 可显著增加半胱天冬酶活化、PARP 裂解、JNK 活化、MnSOD2 诱导和 DNA 损伤。
Carfilzomib (2.0 mg/kg，iv) 与 70 mg/kg Vorinostat 联用几乎消除了 Granta-luciferace 细胞异种移植模型中的肿瘤生长。
| Cell Assay | WST-1 is used to determine the effects of proteasome inhibitors on cell proliferation according to the manufacturer's protocol. The inhibition of proliferation is calculated in relation to parallel control cells that receive vehicle alone and tabulated in KaleidaGraph 3.0.1 or Excel 2000. A linear spline function is used to interpolate the median inhibitory concentration (IC50) using XLfit 4 software. The degree of resistance (DOR) is calculated using the formula: DOR=IC50(resistant cells)/IC50(sensitive cells). |
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| Animal Administration | Animal studies are performed utilizing Beige-nude-XID mice. 10×106 Granta514 cells are pelleted, washed twice with 1X PBS, injected subcutaneously into the right flank. Once the tumors are visible, 5 to 6 mice are treated with carfilzomib±vorinostat and progress of tumor growth or regression is monitored. Stock vorinostat and carfilzomib is dissolved in DMSO and 10% sulfobutylether betacyclodextrin in 10 mM citrate buffer pH respectively. They are stored in −80°C in small aliquots and diluted before injection. |
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化学性质
| 分子量 | 719.91 |
| 分子式 | C40H57N5O7 |
| CAS号 | 868540-17-4 |
| 溶解性（25°C） | DMSO 65 mg/mL |
| 储存条件 | 粉末型式 -20°C 3年；4°C 2年 溶于溶剂 -80°C 6个月；-20°C 1个月 |
| 运输方式 | 冰袋运输，根据产品的不同，可能会有相应调整。 |
储备液配制
*下述溶液配置方法仅为基于分子量计算出的理论值。不同产品在配置溶液前，需考虑其在不同溶剂中的溶解度限制。
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.3891 mL | 6.9453 mL | 13.8906 mL |
| 5 mM | 0.2778 mL | 1.3891 mL | 2.7781 mL |
| 10 mM | 0.1389 mL | 0.6945 mL | 1.3891 mL |
参考文献
[1] Hurchla MA, et al. Leukemia. The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects.
[2] Dasmahapatra G, et al. Mol Cancer Ther. Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo.
[3] Kuhn DJ, et al. Blood. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma.
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