WZ4002 化学構造
分子量: 494.18

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製品説明

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    EGFR製品生物活性の比較
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  • WZ4002のメカニズム

製品の説明

生物活性

製品説明 WZ4002は、EGFR L858RとEGFR L858R/T790Mのための新しい、変異体選択EGFRキナーゼ阻害剤で、 IC50 がそれぞれ 2 nM と 8 nMになる。
ターゲット EGFRL858R EGFRL858R/T790M
IC50 2 nM 8 nM [1]
In vitro試験 WZ4002 inhibits other EGFR genotypes E746_A750 and E746_A750/T790M with IC50 of 2 and 6 nM. Besides, WZ4002 suppresses widetype ERBB2 with an IC50 of 32 nM. WZ4002 inhibits EGFR, AKT and ERK1/2 phosphorylation in NSCLC cell lines and WZ4002 prevents of EGFR phosphorylation in NIH-3T3 cells expressing different EGFR T790M mutant alleles. For WZ4002, kinases that exhibited greater than 95% inhibition relative to the DMSO control at 10 μM are selected for measurement of their dissociation constants. WZ4002, which possesses an ortho-methoxy group at the C2-aniline substituent, is more selective for EGFR compared to WZ3146. WZ4002 is 100-fold less effective at inhibiting phosphorylation of WT EGFR compared to the quinazoline inhibitors. Similarly, WZ4002 prevents EGFR kinase activity of recombinant L858R/T790M protein more potently than of WT EGFR, while the opposite is observed with HKI-272 and gefitinib. [1] In addition, the phosphorylated EGFR of Src TKI-resistant H1975 cells, as well as HCC827 cells, is completely suppressed by the third generation EGFR TKI, WZ4002. [2]
In vivo試験 In a 2-week efficacy study, WZ4002 treatment results in significant tumor regressions compared to vehicle alone in both T790M containing murine models. [1] Treatment with low-dose WZ4002, and high-dose WZ4002 leads to mean decreases in tracer uptake of 26%, and 36%, respectively. [3]
臨床試験
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

EGFR kinase assays In vitro inhibitory enzyme kinetic assays using recombinant EGFR L858R/T790M and WT protein and are performed using the ATP/NADH coupled assay system in a 96-well format. WZ4002 is added to determine its inhibitory effects.

細胞アッセイ: [1]

細胞株 NSCLC, Ba/F3 cells, NIH-3T3 cells, PC9GR4 cells
濃度 0-1 μM
反応時間 72 hours
実験の流れ The NSCLC, Ba/F3 cells, NIH-3T3 cells, PC9GR4 cells are used and verified to contain EGFR delE746_A750/T790M by direct sequencing. Cell proliferation and growth assays are performed using the MTS assay. Site directed mutagenesis is performed using the Quick Change Site-Directed Mutagenesis kit.

動物実験: [1]

動物モデル EGFR-TL (T790M/L858R) mice
製剤 NMP (10% 1-methyl-2-pyrrolidinone: 90% PEG-300
投薬量 25mg/kg
投与方法 Gavage

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 WZ4002 SDF
分子量 494.18
化学式

C25H27ClN6O3

CAS No. 1213269-23-8
保管 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 13 mg/mL (26.3 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 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.
化学名 N-(3-(5-chloro-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yloxy)phenyl)acrylamide

文献中の引用 (13)

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