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WZ4002

Catalog No. S1173 Name Selleck Chemicals
CAS Number 1213269-23-8 Website http://www.selleckchem.com
M. F. C25H27ClN6O3 Telephone (877) 796-6397
M. W. 494.97328 Fax (832) 582-8590
Purity Email sales@selleckchem.com
Storage -20°C Chembase ID: 72557

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 EGFRL858R and EGFRL858R/T790M with IC50 of 2 nM and 8 nM, respectively.
Targets EGFRL858R EGFRL858R/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]
Clinical Trials
Features
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.
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.
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
[1] Zhou W, et al. Nature. 2009, 462(7276), 1070-1074.
[2] Sakuma Y, et al. Lab Invest. 2012, 92(3), 371-383.
[3] Zannetti A, et al. J Nucl Med. 2012, 53(3), 443-450.