1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEWZ4002Cat. No.: HY-12026CAS No.: 1213269-23-8分式: CHClNO分量: 494.97作靶點(diǎn): EGFR作通路: JAK/STAT Signaling; Protein Tyrosine Kinase/RTK儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 100 mg/mL (202.

2、03 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 2.0203 mL 10.1016 mL 20.2032 mL5 mM 0.4041 mL 2.0203 mL 4.0406 mL10 mM 0.2020 mL 1.0102 mL 2.0203 mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲(chǔ)備液，并請(qǐng)注意儲(chǔ)備液的保存式和期限。體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥式選擇適當(dāng)?shù)娜芙獍?，配制前?qǐng)先配制澄清的儲(chǔ)備液，再依次添加助溶劑(為保證實(shí)驗(yàn)結(jié)果的可靠

3、性，體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使；澄清的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請(qǐng)依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.05 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (5.05 mM); Clear solution3. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn o

4、il1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.5 mg/mL (5.05 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 WZ4002是突變選擇性的 EGFR 抑制劑；對(duì)EGFRL858R，EGFRL858R/T790M，EGFRE746_A750，EGFRE746_A750/T790M 的 IC50 值分別為2，8，3，2nM。IC50 & Target EGFRL858R EGFRL858R/T790M EGFRE746_A750 EGFRE746_A750/T790M2

5、 nM (IC50, Cell Assay) 8 nM (IC50, Cell 3 nM (IC50, Cell 2 nM (IC50, Cell Assay)Assay) Assay)體外研究 WZ4002 increases cellular potency correlated with inhibition of EGFR, AKT and ERK1/2 phosphorylation inNSCLC cell lines and EGFR phosphorylation in NIH-3T3 cells expressing different EGFRT790M mutantall

6、eles. WZ4002 inhibits EGFR kinase activity of recombinant L858R/T790M protein more potently than ofWT EGFR 1.體內(nèi)研究 In a pharmacodynamic study WZ4002 effectively inhibits EGFR, AKT and ERK1/2 phosphorylation which isassociated with a significant increase in TUNEL positive and a significant decrease in

7、 Ki67 positive cellscompared to vehicle alone treated mice. In a 2 week efficacy study, WZ4002 treatment results in significanttumor regressions compared to vehicle alone in both T790M containing murine models. Histologicalevaluation of the lungs following treatment confirms significant resolution o

8、f the tumor nodules with only fewsmall residual nodules and nodule remnants that has evidence of treatment effect with decreased cellularityand increased fibrosis consistent with remodeling/scarring 1.PROTOCOLKinase Assay 1 EGFR kinase assay is performed using a GST-kinase fusion protein. The final

9、reaction mixture contained 60mM HEPES pH 7.5, 5 mM MgCl2, 5 mM MnCl2, 3 mM Na3V04, 1.25 mM DTT, 20 M ATP, 1.5 M PTP1B(Tyr66) biotinylated peptide and 50 ng of EGFR kinase. A phospotyrosine mab (pTyr100) is used to detectphosphorylation of the EGFR substrate peptide in the presence of WZ4002, gefitin

10、ib or HKI-272(concentration ranges 0-10 M for all drugs) followed a fluorescent Anti-mouse IgG secondary antibody.Fluorescence emission is detected at 615 nm 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 1 Growth and inhibition of growth

11、is assessed by MTS assay. Ba/F3 cells are exposed to WZ4002 treatment for72 hours. Growth and inhibition of growth is assessed by MTS assay 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Cohorts of EGFR TL/CCSP-rtTA and EGFR TD/CCSP-rtTA are p

12、ut on doxycycline diet at 5 weeks of age toAdministration 1 induce the expression of mutant EGFR. These mice undergo MRI after 6 to 8 weeks of doxycycline diet todocument and quantify the lung cancer burden before being assigned to various treatment study cohorts.2/3 Master of Small Molecules 您邊的抑制劑

13、師www.MedChemEThere is a minimum of 3 mice per treatment group. Mice are then treated either with vehicle (NMP 13 (10%1-methyl-2-pyrrolidinone: 90% PEG-300) alone or WZ4002 at 25mg/kg gavage daily. After 2 weeks oftreatment, these mice undergo a second round of MRI to document their response to the t

14、reatment. MRIsand tumor burden measurement are performed 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Cancer Discov. 2019 Jul;9(7):926-943. Eur J Med Chem. 2017 Oct 20;139:674-697. Oncotarget. 2016 Oct 25;7(43):69760-69769. Oncotarget. 2015 Oct 13;6(31):31313-22. Harvard Medical School LINCS LIBRARYSee more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Zhou W, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.Nature. 2009 Dec