AZD8330 869357-68-6

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Molecular Weight:

461.23 AZD8330 is a novel, selective, non-ATP competitive MEK 1/2 inhibitor with IC50 of 7 nM. Phase 1.


Biological Activity


AZD8330 potently and strongly inhibits MEK 1/2. AZD8330 has no
inhibitory activity against over 200 other kinases including at
concentrations up to 10 μM. AZD8330 demonstrates sub-nanomolar potency
in mechanistic (pERK) and low to sub-nanomolar potency in functional
(proliferation) assays in MEK 1/2 inhibitor sensitive cell lines.


In a Calu-6 rat xenograft pharmacokinetic/pharmacodynamic (PK/PD) model a
single, 1.25 mg/kg oral dose of AZD8330 inhibits ERK phosphorylation by
> 90% for between 4 and 8 hours. Doses as low as 0.4 mg/kg once
daily are sufficient for > 80% tumor growth inhibition in the Calu-6
nude rat xenograft model. In the Calu-6 model, AZD8330 inhibits tumor
growth in a dose-dependent fashion, at 0.3 mg/kg and 1.0 mg/kg once
daily.


Protocol(Only for Reference)


Kinase Assay: [2]

MEK1 enzymatic assays

NH2-terminal hexahistidine tagged, constitutively active MEK1 (S218D, S222D ΔR4F) is expressed in baculovirus-infected Hi5 insect cells and purified by immobilized metal affinity chromatography, ion exchange, and gel filtration. The activity of MEK1 is assessed by measuring the incorporation of [γ- 33P]phosphate from [γ-33P]ATP onto ERK2. The assay is carried out in a 96-well polypropylene plate with an incubation mixture (100 μL) composed of 25 mM HEPES (pH 7.4), 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM sodium orthovanadate, 5 mM DTT, 5 nM MEK1, 1 μM ERK2, and 0 to 80 nM AZD8330 (final concentration of 1% DMSO). The reactions are initiated by the addition of 10 μM ATP (with 0.5 μC k[γ-33P]ATP/well) and incubated at room temperature for 45 min. An equal volume of 25% trichloracetic acid is added to stop the reaction and precipitate the Proteins. Precipitated proteins are trapped onto glass fiber B filter plates, excess labeled ATP is washed off with 0.5% phosphoric acid, and radioactivity is counted in a liquid scintillation counter. ATP dependence is determined by varying the amount of ATP in the reaction mixture. The data are globally fitted.

Cell Assay: [1]

Cell lines	Malme-3M melanoma cells
Concentrations	~10 μM
Incubation Time	1 hour
Method	Malme-3M melanoma cells are plated in 96-wells and treated with various concentrations of AZD8330 for 1 hour at 37 °C. The cells are fixed, permeabilized, and incubated with an anti-phospho-ERK antibody and an anti-ERK 1/2 antibody. Plates are washed and fluorescently-labeled secondary antibodies are added. Plates are analyzed on a LICOR fluorescence imager. The pERK signal is normalized to the total ERK signa

Animal Study: [1]

Animal Models	Female nude rats (NIH rnu/rnu) with Calu-6 cells, nude rats with SW620 cells
Formulation	0.5% HPMC-0.1% Tween
Dosages	0.3 mg/kg, 1 mg/kg
Administration	Oral administration
Solubility	0.5% hydroxyethyl cellulose/0.1% Tween 80, 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)

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)	461.23
Formula	C16H17FIN3O4
CAS No.	869357-68-6

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms	ARRY704

Solubility (25°C) *	In vitro	DMSO	92 mg/mL (199.46 mM)
		Water	<1 mg/mL (
		Ethanol	92 mg/mL (199.46 mM)
	In vivo	0.5% hydroxyethyl cellulose/0.1% Tween 80	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	2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

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Product Categories : MAPK > MEK Inhibitor