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Zosuquidar

 
Catalog No.
A3956
MDR调节剂
组合的产品项目
规格价格库存 数量
5mg
¥ 1,309.00
Ship with 10-15 days
10mg
¥ 2,290.00
Ship with 10-15 days
50mg
¥ 7,090.00
Ship with 10-15 days
100mg
¥ 12,000.00
Ship with 10-15 days

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A

背景

Zosuquidar是一种新型有效的P-糖蛋白调节剂[1]。P-糖蛋白(P-gp)在脑、肝脏、小肠和肿瘤细胞中表达。在肿瘤细胞中,P-糖蛋白(P-gp)作为外排泵发挥功能,负责多药耐药性。肿瘤中P-糖蛋白(Pgp)过表达导致对结构上不相关的溶瘤剂的多药耐药性(MDR)[2]。

体外实验:在CEM/VLB100细胞中,LY335979(0.1 μM)完全恢复细胞对vinblastine、doxorubicin (Dox)、etoposide和Taxol的敏感性。在CEM/VLB100质膜中,LY335979阻断[3H]叠氮基光亲和标记M(r)约170,000的 Pgp,并竞争性抑制[3H]vinblastine与Pgp的结合平衡,Ki值约为0.06 μM[3]。在所有表达P-gp的白血病细胞系中,包括K562/HHT40、K562/HHT90、K562/DOX和HL60/DNR中,Zosuquidar完全或部分恢复药物敏感性。在具有活性P-gp的原代AML母细胞中,Zosuquidar增强anthracyclines (daunorubicin、idarubicin、mitoxantrone)和 gemtuzumab ozogamicin (Mylotarg)的细胞毒性[4]。

在体实验:在携带P388/ADR鼠白血病细胞的小鼠中,LY335979与Dox或etoposide组合治疗显著延长小鼠寿命,药代动力学没有明显改变。在MDR人非小细胞肺癌裸鼠异种移植模型中,LY335979增强Taxol的抗肿瘤活性[3]。

临床试验:在未治疗的非霍奇金淋巴瘤患者中,进行I/II期临床试验研究zosuquidar的安全性和耐受性。在口服三个500 mg剂量的zosuquidar与CHOX组合给药,药物毒性最小,并且没有观察到CHOP相关毒性的增强[5]。在I期研究的晚期实体瘤患者中,zosuquidar(100-300 mg/m2)可以抑制vinorelbine的清除率至适度程度[6]。

参考文献:
Cripe L D, Uno H, Paietta E M, et al.  Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999[J]. Blood, 2010, 116(20): 4077-4085.
Chaudhary P M, Roninson I B.  Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells[J]. Cell, 1991, 66(1): 85-94.
Dantzig A H, Shepard R L, Cao J, et al.  Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979[J]. Cancer Research, 1996, 56(18): 4171-4179.
Tang R, Faussat A M, Perrot J Y, et al.  Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML)[J]. BMC cancer, 2008, 8(1): 1.
Morschhauser F, Zinzani P L, Burgess M, et al.  Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar. 3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin's lymphoma[J]. Leukemia & lymphoma, 2007, 48(4): 708-715.
Lê L H, Moore M J, Siu L L, et al.  Phase I study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours[J]. Cancer chemotherapy and pharmacology, 2005, 56(2): 154-160.

化学属性

StorageStore at -20°C
M.Wt527.6
Cas No.167354-41-8
FormulaC32H31F2N3O2
SynonymsLY335979;LY 335979;LY-335979
SolubilitySoluble in DMSO
Chemical Name(2R)-1-(4-((1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c][7]annulen-6-yl)piperazin-1-yl)-3-(quinolin-5-yloxy)propan-2-ol
SDFDownload SDF
Canonical SMILESFC1([C@@](C2=C([H])C([H])=C([H])C([H])=C23)([H])[C@]1([H])C4=C([H])C([H])=C([H])C([H])=C4C3([H])N5C([H])([H])C([H])([H])N(C([H])([H])[C@@](C([H])([H])OC6=C([H])C([H])=C([H])C7=C6C([H])=C([H])C([H])=N7)([H])O[H])C([H])([H])C5([H])[H])F
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