Zosuquidar (LY335979) 3HCl

Zosuquidar (LY335979) is a potent modulator of P-glycoprotein-mediated multi-drug resistance with Ki of 60 nM. Phase 3.

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Zosuquidar (LY335979) 3HCl Chemical Structure

Zosuquidar (LY335979) 3HCl Chemical Structure
Molecular Weight: 636.99

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Customer Reviews(2)

Quality Control & MSDS

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Product Information

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Product Description

Biological Activity

Description Zosuquidar (LY335979) is a potent modulator of P-glycoprotein-mediated multi-drug resistance with Ki of 60 nM. Phase 3.
Targets P-gp [1]
IC50 60 nM(Ki)
In vitro LY335979 competitively inhibits equilibrium binding of [3H]vinblastine to Pgp by blocking [3H]azidopine photoaffinity labeling of the Pgp in CEM/VLB100 plasma membranes. [1] LY335979 alone shows the cytotoxicity to drug-sensitive and MDR cell lines with IC50 ranging from 6 μM-16 μM and produces its ability to completely reverse the resistance of the oncolytics (vinblastine, doxorubicin, or etoposide) to the MDR cell lines P388/ADR, MCF7/ADR, 2780AD, or UCLA-P3.003VLB at concentration of 0.1 and 0.5 μM. [1] LY335979 significantly restores drug sensitivity in P-gp-expressing leukemia cell lines including K562/HHT40, K562/HHT90, K562/DOX and HL60/DNR, and enhances the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AML blasts with active P-gp. [2] A latest paper indicates that LY335979 completely inhibits apically directed transport of (Z)-endoxifen in the ABCB1-transduced cells. [3]
In vivo
Features

Protocol(Only for Reference)

Kinase Assay: [1]

ATPase Assay P-Glycoprotein ATPase activity is measured by the liberation of inorganic phosphate from ATP. The assay is measured in a 96-well plate for 90 min at 37 °C. Membranes (8 μg-10 μg protein) are incubated in a total volume of 100 μL of buffer A containing 5 mM sodium azide, 1 mM ouabain, 1 mM EGTA, 3 mM ATP, an ATP regenerating system composed of 5 mM phosphoenolpyruvate, and 3.6 units/mL pyruvate kinase in the presence and absence of 1 mM sodium vanadate. Pgp-ATPase activity is defined as the vanadate-sensitive portion of the total ATPase activity. Plates are read 3 minutes after the addition of the detection solution. The absorbance is measured at 690 nm by a microtiter dish reader. A phosphate standard curve is used to calculate the μmol of phosphate formed. Samples are measured in triplicate.

Cell Assay: [1]

Cell lines CEM/VLB100, P388/ADR, MCF7/ADR, 2780AD, and UCLA-P3.OO3VLB cells
Concentrations 0.05 μM to 5 μM
Incubation Time 72 hours
Method Cell viability is determined using a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction method. Cells are harvested during logarithmic growth phase, and seeded in 96-well plates. The cells are then cultured for 72 hours in the presence of oncolytics with or without modulators. MCF-7 and MCF-7/ADR cells are incubated 24 hours before the addition of the drug with and without the LY335979. LY335979 is prepared as 2 nM DMSO stocks and added to wells to give final concentrations ranging from 0.05 to 5 μM. After 72 hours, 20 μL of freshly prepared 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (5 mg/mL in Dulbecco's PBS) is added to each well and incubated for 4 hours in a 37 °C incubator containing 5% CO2. Cells are pelleted in a Sorvall RT6000B centrifuge, 70 μL of medium is carefully removed from each well, and 100 μL of 2-propanol/0.04 N HC1 is added. Cells are resuspended 5-10 times with a Multipipettor or until no particulate matter is visible. Plates are immediately read on a Titertek Multiskan MCC/340 microplate reader Flow Laboratories with a test wavelength of 570 nm and a reference wavelength of 630 nm. Controls are measured in quadruplicate and modulators are measured in duplicate. Cytotoxicity analyses are also performed using the CeliTiter 96 AQueous assay kit.

Animal Study: [1]

Animal Models P388 or P388/ADR cells are implanted by i.p. injection into female BDF1 mice.
Formulation LY335979 is dissolved in 5% mannitol.
Dosages ≤30 mg/kg
Administration Administered via i.p. and i.v.
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Dantzig AH, et al. Cancer Res. 1996, 56(18), 4171-4179.

[2] Tang R, et al. BMC Cancer. 2008, 8,51.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-08-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00233909 Completed Leukemia, Myeloid Kanisa Pharmaceuticals October 2005 Phase 1|Phase 2
NCT00129168 Completed Leukemia, Myeloid Kanisa Pharmaceuticals August 2005 Phase 1|Phase 2
NCT00046930 Completed Leukemia|Myelodysplastic Syndromes Eastern Cooperative Oncology Group|National Cancer Institute (NCI)|Eli Lilly and Company|Kanisa Pharmaceuticals July 2002 Phase 3

Chemical Information

Download Zosuquidar (LY335979) 3HCl SDF
Molecular Weight (MW) 636.99
Formula

C32H31F2N3O2.3HCl

CAS No. 167465-36-3
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 100 mg/mL (156 mM)
Water 23 mg/mL (36 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 1-Piperazineethanol, 4-[(1aα,6α,10bα)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-α-[(5-quinolinyloxy)methyl]-,trihydrochloride

Research Area

Customer Reviews (2)


Click to enlarge
Rating
Source Pharmacol Res, 2013, 67(1):79-83. Zosuquidar (LY335979) 3HCl purchased from Selleck
Method flow cytometry
Cell Lines K562, K562/DoxDR1, K562/DoxDR2, K562/DoxDR3, K562/Dox
Concentrations
Incubation Time
Results Application of P-gp inhibitor Zosuquidar(ZSQ) reversed the resistance to DNR.

Click to enlarge
Rating
Source Pharmacol Res, 2013, 67(1):79-83. Zosuquidar (LY335979) 3HCl purchased from Selleck
Method flow cytometry
Cell Lines K562, K562/DoxDR1, K562/DoxDR2, K562/DoxDR3, K562/Dox
Concentrations
Incubation Time
Results Application of P-gp inhibitor Zosuquidar(ZSQ) reversed the resistance to Nilotinib.

Product Citations (2)

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