OSI-420 183320-51-6

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Molecular Weight:

415.87 OSI-420 is the active metabolite of Erlotinib (EGFR Inhibitor with IC50 of 2 nM).


Biological Activity


OSI-420 is the major metabolite of Erlotinib in human plasma. Erlotinib
disappearance from plasma after a short IV infusion is biexponential
with a mean terminal half-life of 5.2 h and a mean clearance of 128
ml/min per m(2). OSI-420 exposure (AUC) in plasma is 30% (range 12-59%)
of erlotinib, and OSI-420 clearance is more than 5-fold higher than
erlotinib. Erlotinib and OSI-420 are equipotent, and the combined
concentrations of erlotinib + OSI-420 achieved in the CSF exceeded the
IC50 (7.9 ng/ml or 20 nM) for the EGFR tyrosine kinase inhibition in
intact tumor cells.


Erlotinib potently inhibits EGFR
activation in intact cells including HNS human head and neck tumor cells
(IC50 20nM), DiFi humancolon cancer cells andMDA MB-468 human breast
cancer cells. Erlotinib (1 μM) induces Apoptosis in DiFi humancolon
cancer cells. Erlotinib growth of a panel of NSCLC cell
lines including A549, H322, H3255, H358 H661, H1650, H1975, H1299, H596
with IC50 ranging from 29 nM to >20 μM.


Erlotinib(2 μM) significantly inhibits growth of AsPC-1 and BxPC-3 pancreatic cells. The effects of Erlotinib HCl in combination with gemcitabine are
considered additive in KRAS-mutated pancreatic cancer cells. Ten
micromolar of Erlotinib inhibits EGFR phospho-rylation at the Y845
(Src-dependent phosphorylation) and Y1068 (auto-phosphorylation) sites. Combination with Erlotinib could down-modulate rapamycin-stimulated Akt
activity and produces a synergistic effect on cell growth inhibition.


At doses of 100 mg/kg, Erlotinib completely prevents EGF-induced
autophosphorylation of EGFR in human HN5 tumors growing as xenografts in
athymic mice and of the hepatic EGFR of the treated mice. Erlotinib reduces the growth of xenografted human AML cells.


Protocol(Only for Reference)


Kinase Assay: [1]

Kinase Assays

96-well plates are coated by incubation overnight at 37 °C with 100 μL per well of 0.25 mg/mL PGT in PBS. Excess PGT is removed by aspiration, and the plate is washed 3 times with washing buffer (0.1% Tween 20 in PBS). The kinase reaction is performed in 50 μL of 50 mM HEPES (pH 7.3), containing 125 mM sodium chloride, 24 mM magnesium chloride, 0.1 mM sodium orthovanadate, 20 μM ATP, 1.6 μg/mL EGF, and 15 ng of EGFR, affinity purified from A431 cell membranes. Erlotinib HCl in DMSO is added to give a final DMSO concentration of 2.5%. Phosphorylation is initiated by addition of ATP and proceeded for 8 minutes at room temperature, with constant shaking. The kinase reaction is terminated by aspiration of the reaction mixture and is washed 4 times with washing buffer. Phosphorylated PGT is measured by 25 minutes of incubation with 50 μL per well HRP-conjugated PY54 antiphosphotyrosine antibody, diluted to 0.2 μg/mL in blocking buffer (3% BSA and 0.05% Tween 20 in PBS). Antibody is removed by aspiration, and the plate is washed 4 times with washing buffer. The colonmetric signal is developed by addition of TMB Microwell Peroxidase Substrate, 50μL per well, and stopped by the addition of 0.09 M sulfuric acid, 50 μL per well. Phosphotyrosine is estimated by measurement of absorbance at 450 nm. The signal for controls is typically 0.6-1.2 absorbance units, with essentially no back ground in wells without AlP, EGFR, or PGT and is proportional to the time of incubation for 10 minutes.

Cell Assay: [3]

Cell lines	A549, H322, H3255, H358 H661, H1650, H1975, H1299, H596 cells
Concentrations	30 nM-20 μM
Incubation Time	72 hour
Method	Exponentially growing cells are seeded in 96-well plastic plates and exposed to serial dilutions of erlotinib, pemetrexed, or the combination at a constant concentration ratio of 4:1 in triplicates for 72 h. Cell viability is assayed by cell count and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Growth inhibition is expressed as the percentage of surviving cells in drug-treated versus PBS-treated control cells (which is considered as 100% viability). The IC50 value is the concentration resulting in 50% cell growth inhibition by a 72-h exposure to drug(s) compared with untreated control cells and is calculated by the CalcuSyn software.

Animal Study: [7]

Animal Models	Male 5-week-old BALB-nu/nu with HPAC
Formulation	6% Captisol
Dosages	50 mg/kg
Administration	Oral administration

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)	415.87
Formula	C21H21N3O4.HCl
CAS No.	183320-51-6

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms	DesMethyl Erlotinib (CP-473420) HCl

Solubility (25°C) *	In vitro	DMSO	83 mg/mL heating (199.58 mM)
		Water	<1 mg/mL (
		Ethanol	<1 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-(4-(3-ethynylphenylamino)-7-(2-methoxyethoxy)quinazolin-6-yloxy)ethanol hydrochloride

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Product Categories : Protein Tyrosine Kinase > EGFR Inhibitor