WZ4002

Mutant-selective EGFR inhibitor(L858R,T790M), irreversible and potent CAS# 1213269-23-8

WZ4002

Catalog No. BCC1074----Order now to get a substantial discount!

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Chemical structure

WZ4002

3D structure

Chemical Properties of WZ4002

Cas No. 1213269-23-8 SDF Download SDF
PubChem ID 44607530 Appearance Powder
Formula C25H27ClN6O3 M.Wt 495.0
Type of Compound N/A Storage Desiccate at -20°C
Synonyms WZ-4002;WZ 4002
Solubility DMSO : ≥ 100 mg/mL (202.03 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name N-[3-[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]oxyphenyl]prop-2-enamide
SMILES CN1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)OC4=CC=CC(=C4)NC(=O)C=C)Cl)OC
Standard InChIKey ITTRLTNMFYIYPA-UHFFFAOYSA-N
Standard InChI InChI=1S/C25H27ClN6O3/c1-4-23(33)28-17-6-5-7-19(14-17)35-24-20(26)16-27-25(30-24)29-21-9-8-18(15-22(21)34-3)32-12-10-31(2)11-13-32/h4-9,14-16H,1,10-13H2,2-3H3,(H,28,33)(H,27,29,30)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of WZ4002

DescriptionWZ4002 is a novel, mutant-selective inhibitor of EGFR for EGFR(L858R)/(T790M) with IC50 of 2 nM/8 nM.
TargetsEGFRL858REGFRL858R/T790M    
IC502 nM8 nM    

Protocol

Kinase Assay [1]
EGFR kinase assay is performed using a GST-kinase fusion protein. The final reaction mixture contained 60 mM HEPES pH 7.5, 5 mM MgCl2, 5 mM MnCl2, 3 mM Na3V04, 1.25 mM DTT, 20 μM ATP, 1.5 μM PTP1B (Tyr66) biotinylated peptide and 50 ng of EGFR kinase. A phospotyrosine mab (pTyr100) is used to detect phosphorylation of the EGFR substrate peptide in the presence of WZ4002, gefitinib or HKI-272 (concentration ranges 0-10 μM for all drugs) followed a fluorescent Anti-mouse IgG secondary antibody. Fluorescence emission is detected at 615 nm[1].

Cell Assay [1]
Growth and inhibition of growth is assessed by MTS assay. Ba/F3 cells are exposed to WZ4002 treatment for 72 hours. Growth and inhibition of growth is assessed by MTS assay[1].

Animal Administration [1]
Cohorts of EGFR TL/CCSP-rtTA and EGFR TD/CCSP-rtTA are put on doxycycline diet at 5 weeks of age to induce the expression of mutant EGFR. These mice undergo MRI after 6 to 8 weeks of doxycycline diet to document and quantify the lung cancer burden before being assigned to various treatment study cohorts. There 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 of treatment, these mice undergo a second round of MRI to document their response to the treatment. MRIs and tumor burden measurement are performed[1].

References:
[1]. Zhou W, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.Nature. 2009 Dec 24;462(7276):1070-4.

WZ4002 Dilution Calculator

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WZ4002 Molarity Calculator

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Preparing Stock Solutions of WZ4002

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0202 mL 10.101 mL 20.202 mL 40.404 mL 50.5051 mL
5 mM 0.404 mL 2.0202 mL 4.0404 mL 8.0808 mL 10.101 mL
10 mM 0.202 mL 1.0101 mL 2.0202 mL 4.0404 mL 5.0505 mL
50 mM 0.0404 mL 0.202 mL 0.404 mL 0.8081 mL 1.0101 mL
100 mM 0.0202 mL 0.101 mL 0.202 mL 0.404 mL 0.5051 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of WZ4002

1. WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors. Lab Invest. 2012 Mar;92(3):371-83. doi: 10.1038/labinvest.2011.187. Epub 2011 Dec 12.
Abstract
Due to the ability of WZ4002, an EGFR TKI, to suppress phosphorylated EGFR in both H1975 and HCC827 cells, the combination of WZ4002, ABT-263 and TSA almost completely eradicated both the suspended cell lines.

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Background on WZ4002

WZ4002 is a novel mutant-selective epidermal growth factor receptor (EGFR) kinase inhibitor that potently and irreversibly suppresses the ATP-dependent auto-phosphorylation of both wild-type EGFR and EGFR mutants, including EGFR delE746_A750/T790M, EGFR L858R/T790M, EGFR T790M, EGFR delE746_A750 and EGFR L858R, with inhibition constant Ki of 13.6 nM, 1.8 nM, 4 nM, 5 nM, 3.9 nM and 8.5 nM respectively. Although WZ4002 is actively against EGFR mutants rather than wild-type EGFR at lower concentrations resulting in less toxicity in normal tissues, wild-type EGFR is susceptible to higher concentrations of WZ4002 as well as prolonged administration of WZ4002, especially in tissues where it accumulates.

References:
[1]Lee HJ, Schaefer G, Heffron TP, Shao L, Ye X, Sideris S, Malek S, Chan E, Merchant M, La H, Ubhayakar S, Yauch RL, Pirazzoli V, Politi K, Settleman J. Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov. 2013 Feb;3(2):168-81. doi: 10.1158/2159-8290.CD-12-0357. Epub 2012 Dec 10.
[2]Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R, Engen JR, Wong KK, Eck MJ, Gray NS, Jänne PA. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009 Dec 24;462(7276):1070-4. doi: 10.1038/nature08622.
[3]Zannetti A, Iommelli F, Speranza A, Salvatore M, Del Vecchio S. 3'-deoxy-3'-18F-fluorothymidine PET/CT to guide therapy with epidermal growth factor receptor antagonists and Bcl-xL inhibitors in non-small cell lung cancer. J Nucl Med. 2012 Mar;53(3):443-50. doi: 10.2967/jnumed.111.096503. Epub 2012 Feb 13.

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References on WZ4002

WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors.[Pubmed:22157722]

Lab Invest. 2012 Mar;92(3):371-83.

Src has a role in the anoikis resistance in lung adenocarcinomas. We focused on two epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cell lines, HCC827 (E746-A750 deletion) and H1975 (L858R+T790M), in suspension to elucidate whether suspended lung adenocarcinoma cells are eradicated by long-term treatment with Src tyrosine kinase inhibitors (TKIs). We also examined metastasis-positive lymph nodes from 16 EGFR-mutant lung adenocarcinoma patients for immunohistochemical expression of mutant-specific EGFR. Almost all suspended HCC827 cells underwent apoptosis after 144 h of combination treatment with AZD0530, trichostatin A (TSA), and ABT-263, whereas many suspended H1975 cells survived the treatment. AZD0530 is a Src TKI, TSA is a histone deacetylase inhibitor, and ABT-263 is a Bcl-2 inhibitor. During the therapy, the phosphorylation of EGFR decreased in HCC827 cells and remained stable in H1975 cells. The phosphorylated EGFR of Src TKI-resistant H1975 cells, as well as HCC827 cells, was completely suppressed by the third generation EGFR TKI, WZ4002. Consequently, both the suspended cell lines were almost completely eradicated within 144 h, with the combined therapy of WZ4002, ABT-263, and TSA. Interestingly, treated suspended cells underwent apoptosis to a greater extent than did adherent cells. Intrasinus floating lung adenocarcinoma cells in the lymph nodes expressed a mutant-specific EGFR. These findings suggest that suspended EGFR-mutant lung adenocarcinoma cells depend significantly more on EGFR activation for survival than attached cells do. The tumor cells circulating in vessels, which express mutant-specific EGFR, would be highly susceptible to the combination therapy of WZ4002, ABT-263, and TSA.

Description

WZ4002 is a mutant selective EGFR inhibitor with IC50s of 2, 8, 3 and 2 nM for EGFRL858R, EGFRL858R/T790M, EGFRE746_A750 and EGFRE746_A750/T790M, respectively.

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