WZ4002

• Catalog No.: S1173
• CAS Number: 1213269-23-8
• M. F.: C25H27ClN6O3
• M. W.: 494.97328
• Storage: -20°C

SYNONYMS

• IUPAC name: N-{3-[(5-chloro-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)oxy]phenyl}prop-2-enamide
• IUPAC Traditional name: N-{3-[(5-chloro-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)oxy]phenyl}prop-2-enamide

DATABASE IDS

• CAS Number: 1213269-23-8

PROPERTIES

• Target: EGFR
• Salt Data: Free Base
• Solubility: DMSO
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Cancer

Biological Activity

• Description: WZ4002 is a novel, mutant-selective EGFR inhibitor for EGFR^L858R and EGFR^L858R/T790M with IC50 of 2 nM and 8 nM, respectively.
• Targets: EGFR^L858R; EGFR^L858R/T790M
• IC50: 2 nM; 8 nM ^[1]
• In Vitro: 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: 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]

Protocol

• Protocol: Kinase Assay ^[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.
• Protocol: Cell Assay ^[1]
• Cell Lines: NSCLC, Ba/F3 cells, NIH-3T3 cells, PC9GR4 cells
• Concentrations: 0-1 μM
• Incubation Time: 72 hours
• Methods: 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.
• Protocol: Animal Study ^[1]
• Animal Models: EGFR-TL (T790M/L858R) mice
• Formulation: NMP (10% 1-methyl-2-pyrrolidinone: 90% PEG-300
• Doses: 25mg/kg
• Administration: Gavage

References

• References: [1] Zhou W, et al. Nature. 2009, 462(7276), 1070-1074.
• References: [2] Sakuma Y, et al. Lab Invest. 2012, 92(3), 371-383.
• References: [3] Zannetti A, et al. J Nucl Med. 2012, 53(3), 443-450.

REFERENCES

• Zannetti A, et al. J Nucl Med. 2012, 53(3), 443-450.
• Zhou W, et al. Nature. 2009, 462(7276), 1070-1074.
• Sakuma Y, et al. Lab Invest. 2012, 92(3), 371-383.