WZ4002

 

Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

Biological Activity

Description	WZ4002 is a novel, mutant-selective EGFR inhibitor for EGFR(L858R)/(T790M) with IC50 of 2 nM/8 nM; does not inhibit ERBB2 phosphorylation (T798I).
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]
Features

Protocol(Only for Reference)

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
Method	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
Dosages	25mg/kg
Administration	Gavage
Solubility	30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL

1

References

Chemical Information

Download WZ4002 SDF

Chemical Name	N-(3-(5-chloro-2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yloxy)phenyl)acrylamide

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.49418	4.9418	9.8836	-

Customer Reviews (4)

Click to enlarge	Rating
	Source	Mol Cancer Ther, 2012 Oct, 11(10), 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)

Product Citations (9)

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  Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. [Red Brewer M, et al. Proc Natl Acad Sci U S A 2013;110(38):E3595-604]

  
  PubMed: 24019492


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  Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer. [Wang W, et al. Clin Cancer Res 2012;18(6):1663-71]

  
  PubMed: 22317763


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  Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations. [Yamada T , et al. Oncogene 2013;32(37):4427-35]

  
  PubMed: 23045273