WZ4002 化学構造
分子量: 494.18

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Quality Control & MSDS

製品説明

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    EGFR製品生物活性の比較
  • 研究分野
  • 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 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 13 mg/mL (26.3 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
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

カスタマーフィードバック (4)


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Rating
Source Mol Cancer Ther, 2012, 11, 2149-57. WZ4002 purchased from Selleck
Method Tumor volume assay
Cell Lines SCID mice
Concentrations 25 mg/kg
Incubation Time 14 -21 d
Results Treatment with WZ4002 completely inhibited the growth of PC-9/Vec tumors, whereas treatment with E7050 did not (Fig. A). Treatment with either agent a lone slightly suppressed the growth of PC- 9/HGF#5 t umor s ( Fig. B). Importantly, the combination of WZ4002 and E7050 reduced the size of PC-9/HGF#5 tumors(Fig.B).These results suggest that HGF can induce resistance to WZ4002 in vivo and that this resistance can be overcome by E7050. In the second model, the growth of tumors induced by H1975 cells, which carry a T790M second mutation, was inhibited by WZ4002 (Fig. C), In the third model, in which resistance was induced by Met amplification, monotherapy with either WZ4002 or E7050 partially inhibited the growth of HCC827ER tumors(Fig. D)

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Rating
Source Lab Invest, 2011, 92, 371-383. WZ4002 purchased from Selleck
Method Western blot
Cell Lines H1975 parental or SR cells
Concentrations 0-1 μM
Incubation Time 24 h
Results WZ4002 substantially reduced the phosphorylation levels of EGFR in H1975 SR cells, as well as parental cells in almost the same way (Figure 4a). However, the sensitivity of H1975 SR cells to WZ4002-induced apoptosis was considerably lower than parental cells

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Rating
Source Lab Invest, 2011, 92, 371-383. WZ4002 purchased from Selleck
Method Caspase-Glo 3/7 assay
Cell Lines H1975 SR cells, HCC827 cells
Concentrations
Incubation Time 24 h
Results Short-term (24 h) treatment with the three drugs induced much more apoptosis in H1975 SR cells than the combined therapy with WZ4002 and ABT-263 in terms of caspase 3/7 activation assay.

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Rating
Source Dr. Yong-Weon Yi from Georgetown University Medical Center. WZ4002 purchased from Selleck
Method MTT assays
Cell Lines
Concentrations 0-10 μM
Incubation Time 72 h
Results WZ4002 potently inhibited the survival of UWB1-289 cells and LN-428-BRCA1-KD cells.

文献中の引用 (13)

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