Zosuquidar (LY335979) 3HCl 167465-36-3

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Molecular Weight: 636.99 Zosuquidar (LY335979) is a potent modulator of P-glycoprotein-mediated multi-drug resistance with Ki of 60 nM. Phase 3.


LY335979 competitively inhibits equilibrium binding of [3H]vinblastine to Pgp by blocking [3H]azidopine photoaffinity labeling of the Pgp in CEM/VLB100 plasma membranes. 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.


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. A latest paper
indicates that LY335979 completely inhibits apically directed transport
of (Z)-endoxifen in the ABCB1-transduced cells.






Protocol(Only for Reference)Kinase Assay:

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 mM 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.

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

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

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)

Chemical Information

Molecular Weight (MW)	636.99
Formula	C32H31F2N3O2.3HCl
CAS No.	167465-36-3

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	100 mg/mL (156.98 mM)
		Water	23 mg/mL (36.1 mM)
		Ethanol	<1 mg/mL (
	In vivo	30% PEG400/0.5% Tween80/5% propylene glycol	30 mg/mL

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

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Product Categories : Neuronal Signaling > P-gp Inhibitor