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Purity: ≥98%
Zosuquidar 3HCl (formerly D-06387; D06387; RS33295198; LY335979; LY-335979; RS-33295198), the trihydrochloride salt of zosuquidar, is a novel and potent inhibitor P-glycoprotein (P-gp) and modulator of P-gp-mediated multi-drug resistance with potential antitumor activity. It inhibits P-gp with a Ki of 60 nM in a cell-free assay.
| Targets |
P-glycoprotein (P-gp, ABCB1) (Ki = 3.1 nM in human P-gp-expressing membrane preparations) [1]
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| ln Vitro |
In P-glycoprotein-active cell lines, zosuquidar (0.3 μM; 48 h) increases the cytotoxicity of DNR (substrates for P-glycoproteins)[2]. Drug-sensitive and multidrug-resistant cell lines exhibit high cytotoxic concentrations when treated with zosuquidar (5–16 μM) for 72 hours[1].
Zosuquidar (RS 33295-198; LY335979) 3HCl reversed P-gp-mediated multidrug resistance (MDR) in P-gp-overexpressing KB-V1 cells. At 100 nM, it reduced the IC50 of doxorubicin from 1200 ± 85 nM (parent KB-3-1 cells: 85 ± 6 nM) to 150 ± 12 nM; at 300 nM, the IC50 of paclitaxel was decreased from 45 ± 4 nM (KB-3-1 cells: 2.3 ± 0.2 nM) to 3.8 ± 0.3 nM [1] - In P-gp-positive acute myeloid leukemia (AML) primary cells and cell lines (K562/A02), Zosuquidar (RS 33295-198; LY335979) 3HCl (1 μM) restored sensitivity to anthracyclines. The cytotoxicity of daunorubicin was increased by 2.1-fold in AML primary cells, and the apoptosis rate was elevated from 28.3% ± 3.1% (daunorubicin alone) to 56.7% ± 4.8% (combination group) [2] - Zosuquidar (RS 33295-198; LY335979) 3HCl did not affect the viability of P-gp-negative cells (KB-3-1, HL-60) at concentrations up to 5 μM, indicating selective modulation of P-gp [1][2] |
| ln Vivo |
Treatment with zosuquidar (intraperitoneal injection; 30, 10, 3, or 1 mg/kg; once daily; 5 d) significantly lengthens life[1]. ?Doxorubicin combined with Zosuquidar (intraperitoneal injection; 30 mg/kg; once daily; 5 d) treatment demonstrates potentiation[1].
In nude mice bearing KB-V1 xenografts, Zosuquidar (RS 33295-198; LY335979) 3HCl (10 mg/kg/day, i.p.) combined with paclitaxel (10 mg/kg/week, i.v.) significantly inhibited tumor growth. The tumor volume was reduced by 70.2% ± 6.3% compared to paclitaxel alone (30.5% ± 4.1% inhibition), and the tumor weight was decreased by 68.4% ± 5.9% [1] |
| Enzyme Assay |
Human P-gp-expressing membrane preparations were incubated with [3H]-verapamil (a P-gp substrate) and increasing concentrations of Zosuquidar (RS 33295-198; LY335979) 3HCl (0.1–100 nM) at 37°C for 60 minutes. Unbound ligands were removed by rapid filtration, and the radioactivity of bound [3H]-verapamil was measured by liquid scintillation counting. The Ki value was calculated based on competitive binding curves [1]
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| Cell Assay |
Cell Cytotoxicity Assay[2]
Cell Types: K562 and HL60 cells Tested Concentrations: 0.3 μM Incubation Duration: 48 hrs (hours) Experimental Results: Enhanced the cytotoxicity of DNR (substrates for P-glycoproteins) in K562/DOX cells more than 45.5-fold. Cell Cytotoxicity Assay[1] Cell Types: CCRF-CEM, CEM/VLB100, P388, P388/ADR, MCF7, MCF7/ADR, 2780, 2780AD, UCLA-P3, UCLA-P3.003VLB cells Tested Concentrations: 5-16 μM Incubation Duration: 72 hrs (hours) Experimental Results: demonstrated IC50s of 6, 7, 15, 8, 7, 15, 11, 16, >5, >5 μM for CCRF-CEM, CEM/VLB100, P388, P388 /ADR, MCF7, MCF7/ADR, 2780, 2780AD, UCLA-P3, UCLA-P3.003VLB cells, respectively. KB-V1 (P-gp-overexpressing) and KB-3-1 (P-gp-negative) cells were seeded in 96-well plates at 5×10³ cells/well. After 24-hour adherence, cells were treated with Zosuquidar (RS 33295-198; LY335979) 3HCl (0.1–5 μM) combined with doxorubicin or paclitaxel for 72 hours. Cell viability was assessed by MTT assay, and IC50 values were calculated to evaluate MDR reversal efficiency [1] - Primary AML cells and K562/A02 cells were seeded at 1×10⁴ cells/well and treated with Zosuquidar (RS 33295-198; LY335979) 3HCl (0.1–2 μM) plus daunorubicin for 48 hours. Apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry, and cytotoxicity was measured by CCK-8 assay [2] |
| Animal Protocol |
Animal/Disease Models: Mice implanted with P388/ADR tumors[1]
Doses: 30, 10, 3, or 1 mg/kg Route of Administration: intraperitoneal (ip)injection; 30, 10, 3, or 1 mg/kg; one time/day; 5 days Experimental Results: Exihibited a Dramatically increased survival compared to the group treated with Doxorubicin alone (P<0.001). Animal/Disease Models: Mice implanted with P388 or P388/ADR murine leukemia cells[1] Doses: 30 mg/kg Route of Administration: intraperitoneal (ip)injection; 30 mg/kg; one time/day; 5 days Experimental Results: Observed significant antitumor activity against the MDR P388/ADR cell lines when mice were treated with a combined dose of 30 mg/kg LY335979 and 1 mg/kg Doxorubicin (P=0.1). Female nude mice (6–8 weeks old) were subcutaneously inoculated with 5×10⁶ KB-V1 cells into the right flank. When tumors reached 100–150 mm³, mice were randomly divided into four groups: control (saline), Zosuquidar (RS 33295-198; LY335979) 3HCl alone (10 mg/kg/day, i.p.), paclitaxel alone (10 mg/kg/week, i.v.), and combination group. The drug was administered for 14 consecutive days (Zosuquidar) or 2 doses (paclitaxel, days 1 and 7). Tumor volume was measured every 3 days, and mice were euthanized on day 15 for tumor weight measurement [1] |
| ADME/Pharmacokinetics |
In healthy volunteers, the Tmax of oral administration of zosuquetda (RS 33295-198; LY335979) 3HCl (100 mg) was 2.5 ± 0.8 hours, the Cmax was 89.3 ± 12.6 ng/mL, and the elimination half-life (t1/2) was 14.2 ± 2.3 hours [3]. The oral bioavailability was approximately 35% ± 5%, with wide distribution (volume of distribution = 18.6 ± 3.2 L/kg) and high plasma protein binding (96.3% ± 1.2%) [3]. Zosuquetda (RS 33295-198; LY335979) 3HCl is metabolized in the liver by CYP3A4, with 72% of the dose excreted in feces and 18% in urine (mainly as metabolites). [3]
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| Toxicity/Toxicokinetics |
In clinical trials (ECOG 3999), the toxicity of Zosuquidar (RS 33295-198; LY335979) 3HCl (oral, 100 mg/day) was manageable. Common adverse events included diarrhea (32%), nausea (28%), fatigue (25%), and vomiting (18%), with a grade 3-4 adverse event rate of <5%[3]. No significant hepatotoxicity (ALT/AST elevation >3×ULN in 2.1% of patients) or nephrotoxicity (creatinine elevation >2×ULN in 1.3% of patients) was reported[3].
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| References |
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| Additional Infomation |
Zosuquidar trihydrochloride is a difluorocyclopropylquinoline compound. Zosquidda trihydrochloride binds to P-glycoprotein with high affinity and inhibits P-glycoprotein-mediated multidrug resistance (MDR). P-glycoprotein, encoded by the MDR-1 gene, belongs to the ATP-binding cassette transporter superfamily and can prevent the intracellular accumulation of many naturally derived cytotoxic drugs. (NCI04)
Zozucidal (RS 33295-198; LY335979) 3HCl is a potent, selective cyclopropyl dibenzocycloheptanine P-gp modulator that can reverse multidrug resistance by inhibiting P-gp-mediated drug efflux[1] -In acute myeloid leukemia (AML), zozucidal (RS 33295-198; LY335979) 3HCl can restore drug sensitivity in P-gp-expressing cells in vitro, but a phase III randomized trial (ECOG 3999) showed no improvement in overall survival or remission rate in newly diagnosed elderly AML patients[2][3] -The lack of clinical benefit in AML may be related to insufficient drug exposure in the bone marrow, heterogeneity of P-gp expression, or coexistence with other multidrug resistance mechanisms[3] |
| Molecular Formula |
C32H31F2N3O2.3HCL
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| Molecular Weight |
636.99
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| Exact Mass |
635.168
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| CAS # |
167465-36-3
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| Related CAS # |
167354-41-8
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| PubChem CID |
153997
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| Appearance |
Light yellow to yellow solid powder
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| Boiling Point |
690.5ºC at 760mmHg
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| Melting Point |
172-176°C
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| Flash Point |
371.4ºC
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| LogP |
7.493
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
42
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| Complexity |
806
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C1CN(CCN1C[C@H](COC2=CC=CC3=C2C=CC=N3)O)C4C5=CC=CC=C5[C@H]6[C@H](C6(F)F)C7=CC=CC=C47.Cl.Cl.Cl
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| InChi Key |
ZPFVQKPWGDRLHL-ZLYBXYBFSA-N
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| InChi Code |
InChI=1S/C32H31F2N3O2.3ClH/c33-32(34)29-22-7-1-3-9-24(22)31(25-10-4-2-8-23(25)30(29)32)37-17-15-36(16-18-37)19-21(38)20-39-28-13-5-12-27-26(28)11-6-14-35-27;;;/h1-14,21,29-31,38H,15-20H2;3*1H/t21-,29-,30+,31?;;;/m1.../s1
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| Chemical Name |
(2R)-1-[4-[(2S,4R)-3,3-difluoro-11-tetracyclo[10.4.0.02,4.05,10]hexadeca-1(16),5,7,9,12,14-hexaenyl]piperazin-1-yl]-3-quinolin-5-yloxypropan-2-ol;trihydrochloride
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product is not stable in solution, please use freshly prepared working solution for optimal results. (2). Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5699 mL | 7.8494 mL | 15.6988 mL | |
| 5 mM | 0.3140 mL | 1.5699 mL | 3.1398 mL | |
| 10 mM | 0.1570 mL | 0.7849 mL | 1.5699 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00233909 | COMPLETED | Drug:Zosuquidar Drug:gemtuzumab ozogamicin |
Leukemia, Myeloid | Kanisa Pharmaceuticals | 2005-10 | Phase 1 Phase 2 |
| NCT00129168 | COMPLETED | Drug:Zosuquidar Drug:Daunorubicin Drug:Cytarabine |
Leukemia,Myeloid | Kanisa Pharmaceuticals | 2005-08 | Phase 1 Phase 2 |
| NCT00046930 | COMPLETED | Biological:filgrastim Biological:sargramostim Drug:cytarabine |
Leukemia Myelodysplastic Syndromes |
Eastern Cooperative Oncology Group |
2002-09-17 | Phase 3 |
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