ArtNr |
S2826-25 |
Hersteller |
Selleckchem
|
CAS-Nr. |
183321-86-0, 183320-51-6 (HCl) |
Menge |
25 mg |
Kategorie |
|
Typ |
Inhibitors |
Specific against |
other |
ECLASS 10.1 |
32160490 |
ECLASS 11.0 |
32160490 |
UNSPSC |
12000000 |
Similar products |
Desmethyl, 183321-86-0 |
Lieferbar |
|
Administration |
Oral administration |
Animal Models |
Male 5-week-old BALB-nu/nu with HPAC |
Cell lines |
A549, H322, H3255, H358 H661, H1650, H1975, H1299, H596 |
Chemical Name |
2-(4-(3-ethynylphenylamino)-7-(2-methoxyethoxy)quinazolin-6-yloxy)ethanol |
Clinical Trials |
Phase 1 Study of Erlotinib Prior to Surgery in Patients With Head and Neck Cancer is ongoing. |
Concentrations |
30 nM-20 uM |
Description |
Desmethyl Erlotinib (CP-473420) is a free base of OSI-420, which is an active metabolite of Erlotinib which is an orally active EGFR inhibitor for human EGFR with IC50 of 2 nM. |
Dosages |
50 mg/kg |
Formulation |
6% Captisol |
IC50 |
2 nM[1], 2 nM[1], 2 nM[1], 2 nM[1], 2 nM[1], 2 nM[1] |
In vitro |
OSI-420 is the major metabolite of Erlotinib in human plasma. Erlotinib disappearance from plasma after a short IV infusion was 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 was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was 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.[1] 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 uM) induces apoptosis in, DiFi humancolon cancer cells.[2] 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 uM.[3] Erlotinib(2 uM) significantly inhibits growth of AsPC-1 and BxPC-3 pancreatic cells.[4] 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.[5] Combination with Erlotinib could down-modulate rapamycin-stimulated Akt activity and produces a synergistic effect on cell growth inhibition.[6] |
In vivo |
At doses of 100 mg/kg, Erlotinib HCl 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.[2] Erlotinib HCl (100 mg/Kg) inhibits H460a and A549 tumor models with 71 and 93% inhibition rate.[6] |
Incubation Time |
72 hour |
Kinase Assay |
[2], Kinase assays, 96-well plates are coated by incubation overnight at 37 C with 100 uL 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 uL of 50 mM HEPES (pH 7.3), containing 125 mM sodium chloride, 24 mM magnesium chloride, 0.1 mM sodium orthovanadate, 20 uM ATP, 1.6 ug/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 uL per well HRP-conjugated PY54 antiphosphotyrosine antibody, diluted to 0.2 ug/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, 50uL per well, and stopped by the addition of 0.09 M sulfuric acid, 50 uL 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. |
Method |
Exponentially growing cells were 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 was assayed by cell count and the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Growth inhibition was expressed as the percentage of surviving cells in drug-treated versus PBS-treated control cells (which was considered as 100% viability). The IC50 value was the concentration resulting in 50% cell growth inhibition by a 72-h exposure to drug(s) compared with untreated control cells and was calculated by the CalcuSyn software. |
Molecular Weight (MW) |
379, 41 |
Picture ChemicalStructure Description |
Desmethyl Erlotinib (CP-473420) Chemical Structure |
Solubility (25C) |
DMSO 11 mg/mL, Water <1 mg/mL, Ethanol 5 mg/mL |
Storage |
2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO |
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