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Zosuquidar
本产品不向个人销售，仅用作科学研究，不用于任何人体实验及非科研性质的动物实验。
Zosuquidar图片
CAS NO:167354-41-8
包装与价格：
包装价格(元)
5mg电议
10mg电议
50mg电议
100mg电议

产品介绍
Zosuquidar (LY335979) 是一种 P-糖蛋白 (P-gp) 抑制剂 (Ki=59 nM)。 Zosuquidar 具有抗肿瘤活性，可用于急性髓性白血病 (AML) 研究。
Cas No.167354-41-8
别名(2R)-1-{4-[(1AR,6R,10BS)-1,1-二氟-1,1A,6,10B-四氢二苯并[A,E]环丙并[C]环庚烯-6-基]哌嗪-1-基}-3-(喹啉-5-基氧基)丙-2-醇,LY335979;LY 335979;LY-335979
化学名(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
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
分子式C32H31F2N3O2
分子量527.6
溶解度Soluble in DMSO
储存条件Store at -20℃
General tipsFor obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.
Shipping ConditionEvaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request
产品描述

Zosuquidar (LY335979) 3HCl is a novel and potent modulator of P-glycoprotein (P-gp) [1]. P-gp is wildly expressed in brain, liver, small intestine and tumor cells and acts as an efflux pump responsible for multidrug resistance in tumor cells. Overexpression of Pgp in tumors results in multidrug resistance (MDR) to structurally unrelated oncolytics [2].

In vitro: In CEM/VLB100 cells, LY335979 treatment (0.1 μM) fully restored the sensitivity to vinblastine, doxorubicin (Dox), etoposide, and Taxol. In CEM/VLB100 plasma membranes, LY335979 blocked [3H]azidopinephotoaffinity labeling of the M(r) approximately 170,000 Pgp and competitively inhibited equilibrium binding of [3H]vinblastine to Pgp with the Ki value of approximately 0.06 μM [3]. In all P-gp-expressing leukemia cell linesincluding K562/HHT40, K562/HHT90, K562/DOX and HL60/DNR, Zosuquidar completely or partially restored drug sensitivity. In primary AML blasts with active P-gp, Zosuquidar enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumabozogamicin (Mylotarg)[4].

In vivo: In mice bearing P388/ADR murine leukemia cells,treatment with LY335979 in combination with Dox or etoposide significantly increased in life span with no apparent alteration of pharmacokinetics. In a MDR human non-small cell lung carcinoma nude mouse xenograft model, LY335979 enhanced the antitumor activity of Taxol [3].

Clinical trials: In patients with untreated non-Hodgkin's lymphoma,a phase I/II trial was conducted to investigate the safety and tolerance of zosuquidar. In patients giving three doses of 500 mg of zosuquidar p.o. in combination with CHOX, toxicity was minimal and no enhancement of CHOP-related toxicity was observed [5]. In patients with advanced solid tumours in Phase I study, zosuquidar(100–300 mg/m2) can inhibit vinorelbine clearance to a modest degree[6].

References:
[1] 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.
[2] 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.
[3] 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.
[3] 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.
[4] 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.
[5] 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.