CEP-32496 1188910-76-0

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Molecular Weight:

517.46 CEP-32496 is a highly Potent Inhibitor of BRAF(V600E/WT) and c-Raf with Kd of 14 nM/36 nM and 39 nM, also potent to Abl-1, c-Kit, Ret, PDGFRβ and VEGFR2, respectively; insignificant affinity for MEK-1, MEK-2, ERK-1 and ERK-2. Phase 1/2.


Biological Activity


CEP-32496 inhibits A375 cell (BRAFV600E) proliferation with
EC50 of 78 nM. CEP-32496 exhibits more sensitive cytotoxicity for tumor
cell lines (A375, SK-MEL-28, Colo-205, Colo-679, and HT-144) expressing
mutant BRAF than those expressing wild-type BRAF (HCT116, Hs578T, LNCaP,
DU145, and PC-3). CEP-32496 inhibits mitogen-activated protein
(MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation
(pMEK) in human melanoma (A375) and colorectal cancer (Colo-205) cell
lines with IC50 of 78 nM and 60 nM, respectively.


CEP-32496 exhibits good stability in mouse, dog, monkey, and human liver
microsomal preparations with measured intrinsic clearance values of 1/2
> 60 min in all assays. CEP-32496 (30 mg/kg, orally, BID) exhibits
tumor stasis and a 40% incidence of partial tumor regressions (PRs) in
Colo-205 xenograft mouse model, whereas the 100 mg/kg dose group
exhibits both tumor stasis and an 80% incidence of PRs.


CEP-32496 (30
mg/kg, orally, BID) leads to a 50% and 75% inhibition of normalized pMEK
in tumor lysates at the 2 hours and 6 hours postdose time point,
respectively, while a 55 mg/kg dose results in a 75% to 57% inhibition
of pMEK at 2 hours through 10 hours post administration in Colo-205
xenograft mouse model. CEP-32496 is orally bioavailable in multiple
preclinical species (>95% in rats, dogs, and monkeys). CEP-32496 (100
mg/kg) results in inhibition of pMEK and pERK and sustained tumor
stasis and regressions in BRAF(V600E) colon carcinoma xenografts in nude
mice.


Protocol(Only for Reference)


Kinase Assay: [1]

Binding assay

Kinases are produced displayed on T7 phage or by expression in HEK-293 cells and tagged with DNA. Binding reactions are performed at room temperature for 1 hour, and the fraction of kinase not bound to test compound is determined by capture with an immobilized affinity ligand and quantitation by quantitative PCR. Each kinase is tested individually against CEP-32496. Kd values are determined using eleven serial 3-fold dilutions and presented as mean values from experiments performed in duplicate. Variability between individual values is less than 2-fold.

Cell Assay: [1]

Cell lines	A375 cell lines
Concentrations	78 nM
Incubation Time	72 hours
Method	Cells are seeded at 104 cells per well in DMEM with 10% fetal calf serum and allowed to attach. The cells are washed with PBS and switched to DMEM with 0.5% of serum and incubated overnight. CEP-32496 is then added at various concentrations with a final DMSO concentration of 0.5% and incubated for 72 h. At the end of incubation, a Cell Titer Blue is added per instructions, and incubation is continued for 3 hours. Remaining viable cells are quantified by measuring the strength of the fluorescence signal using SoftMax Pro (excitation at 560 nm and emission at 590 nm). IC50 values are derived using a 9-point curve fitted with Igor Pro and are presented as mean values from experiments performed in duplicate. Variability between individual values is less than 2-fold.

Animal Study: [1]

Animal Models	Colo-205 xenograft mouse model
Formulation	22% HPβCD
Dosages	100 mg/kg
Administration	oral gavage
Solubility	15% Captisol, 15 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)	517.46
Formula	C24H22F3N5O5
CAS No.	1188910-76-0

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

Solubility (25°C) *	In vitro	DMSO	9 mg/mL (17.39 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	15% Captisol	15 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	Urea, N-[3-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl]-N-[5-(2,2,2-trifluoro-1,1-dimethylethyl)-3-isoxazolyl]-

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