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LY335979

Catalog No. S1481 Name Selleck Chemicals
CAS Number 167465-36-3 Website http://www.selleckchem.com
M. F. C32H34Cl3F2N3O2 Telephone (877) 796-6397
M. W. 636.9870664 Fax (832) 582-8590
Purity Email sales@selleckchem.com
Storage -20°C Chembase ID: 72703

SYNONYMS

IUPAC name
(2R)-1-{4-[(2R,4S,11S)-3,3-difluorotetracyclo[10.4.0.0^{2,4}.0^{5,10}]hexadeca-1(12),5(10),6,8,13,15-hexaen-11-yl]piperazin-1-yl}-3-(quinolin-5-yloxy)propan-2-ol trihydrochloride
IUPAC Traditional name
(2R)-1-{4-[(2R,4S,11S)-3,3-difluorotetracyclo[10.4.0.0^{2,4}.0^{5,10}]hexadeca-1(12),5(10),6,8,13,15-hexaen-11-yl]piperazin-1-yl}-3-(quinolin-5-yloxy)propan-2-ol trihydrochloride
Synonyms
Zosuquidar trihydrochloride
RS-33295-198

DATABASE IDS

CAS Number 167465-36-3

PROPERTIES

Target P-gp
Salt Data HCL
Storage Condition -20°C

DETAILS

Description (English)
Research Area
Description Cancer
Biological Activity
Description LY335979 (Zosuquidar) is a potent modulator of P-glycoprotein-mediated multidrug resistance with Ki of 60 nM.
Targets P-glycoprotein
IC50 60 nM (Ki) [1]
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
Clinical Trials
Features
Combination Therapy
Description In the MDR P388/ADR mouse model, combined treatment of LY335979 (30 mg/kg) and doxorubicin (1 mg/kg) exhibits a significant antitumor activity than doxorubicin alone. In UCLA-P3.003VLB human non-small cell lung carcinoma xenografts model, combined treatment of Taxol (20 mg/kg) and LY335979 (30 mg/kg) leads to a significant suppression of solid tumor growth compared to either treatment given alone. [1]
Protocol
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
Methods 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.
Doses ≤30 mg/kg
Administration Administered via i.p. and i.v.
References
[1] Dantzig AH, et al. Cancer Res. 1996, 56(18), 4171-4179.
[2] Tang R, et al. BMC Cancer. 2008, 8,51.
[3] Iusuf D, J Pharmacol Exp Ther. 2011, 337(3), 710-717.