OSI-420 化学構造
分子量: 415.87

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Quality Control & MSDS

製品説明

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製品の説明

生物活性

製品説明 OSI-420は、人間のEGFRとEGFR自己リン酸化の抑制のための経口で有効なEGFR チロシンキナーゼ阻害剤であるErlotinibの活性代謝物質で、IC50 がそれぞれ 2 nM と 20 nMです。
ターゲット

EGFR

IC50

2 nM [1]

In vitro試験 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. [1] Erlotinib potently inhibits EGFR activation in intact cells including HNS human head and neck tumor cells (IC50 20nM), DiFi human colon cancer cells andMDA MB-468 human breast cancer cells. Erlotinib (1 μM) induces apoptosis in DiFi human colon cancer cells. [2] Erlotinib inhibits 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. [3] Erlotinib(2 μM) 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試験 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. [1] Erlotinib reduces the growth of xenografted human AML cells. [4]
臨床試験 Erlotinib has entered in a phase II clinical trial in the treatment of primary sclerosing cholangitis, cholangiocarcinoma and chemoprevention.
特集 OSI 420 is a major active metabolite of Erlotinib.

プロトコル (参考用のみ)

キナーゼアッセイ:

[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.

細胞アッセイ:

[3]

細胞株 A549, H322, H3255, H358 H661, H1650, H1975, H1299, H596 cells
濃度 30 nM-20 μM
反応時間 72 hour
実験の流れ

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.

動物実験:

[7]

動物モデル Male 5-week-old BALB-nu/nu mice with HPAC
製剤 6% Captisol
投薬量 50 mg/kg
投与方法 Oral administration

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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)
1

参考

化学情報

Download OSI-420 SDF
分子量 415.87
化学式

C21H21N3O4.HCl

CAS No. 183320-51-6
保管 2年-20℃
6月-80℃in solvent
別名 DesMethyl Erlotinib (CP-473420) HCl
溶解度 (25°C) * In vitro DMSO 83 mg/mL warmed (199.58 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
* <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.
化学名 2-(4-(3-ethynylphenylamino)-7-(2-methoxyethoxy)quinazolin-6-yloxy)ethanol hydrochloride

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Rating
Source Sci Pharm, 2012, 80, 633-646 . OSI-420 purchased from Selleck
Method LC-MS/MS analysis
Cell Lines Wistar rats
Concentrations 1.5-1150 ng/mL
Incubation Time 24 h, 12h
Results An LC-MS/MS bioanalytical method for the simultaneous determination of three analytes, CCB, ERT, and OSI-420, was developed and validated in rat plasma. The method was good enough to detect the low concentration of 1.5 ng/mL for all analytes in 50 µL rat plasma, and can further be improved by increasing the plasma volume.

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