Home Protein Tyrosine Kinase EGFR inhibitor WZ4002

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WZ4002 EGFR inhibitor

Cat.No.S1173

WZ4002 is a novel, mutant-selective EGFR inhibitor for EGFR(L858R)/(T790M) with IC50 of 2 nM/8 nM in BaF3 cell line; this compound does not inhibit ERBB2 phosphorylation (T798I).
WZ4002 EGFR inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 494.18

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Quality Control

Batch: Purity: 99.98%
99.98

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Sf9 cells Function assay 60 mins Inhibition of EGFR L858R mutant (unknown origin) expressed in Sf9 cells pre-incubated for 60 mins before substrate and ATP addition by homogeneous time-resolved FRET assay, IC50=1 nM
mouse BA/F3 cells Proliferation assay Antiproliferative activity against mouse BA/F3 cells transfected with EGFR E746_A750_del/T790M mutant, EC50=2 nM
human HCC827 cells Proliferation assay 72 h Antiproliferative activity against human HCC827 cells harboring EGFR del E746-A750 mutant after 72 hrs by MTS assay, IC50=7 nM
human PC9 cells Proliferation assay Antiproliferative activity against growth-resistant human PC9 cells expressing EGFR E746_A750/T790M mutant, EC50=14 nM
NCI-H1975 cells Function assay 2 h Inhibition of EGFR L858R/T970M double mutant phosphorylation in human NCI-H1975 cells after 2 hrs by fluorescence assay, IC50=0.023 μM
human 16HBE cells Proliferation assay 72 h Antiproliferative activity against human 16HBE cells expressing wild type EGFR after 72 hrs by MTT assay, IC50=0.811 μM
human A431 cells Cytotoxicity assay 72 h Cytotoxicity against human A431 cells overexpressing wild type EGFR assessed as growth inhibition after 72 hrs by MTT assay, IC50=1.108 μM
human LoVo cells Function assay 2 h Inhibition of wild type EGFR phosphorylation in human LoVo cells after 2 hrs by fluorescence assay, IC50=1.18 μM
human 16HBE14o- cells  Cytotoxicity assay 72 h Cytotoxicity against human 16HBE14o- cells harboring wild type EGFR assessed as growth inhibition after 72 hrs by MTT assay, IC50=1.355 μM
human BEAS2B cells Cytotoxicity assay 72 h Cytotoxicity against human BEAS2B cells harboring wild type EGFR assessed as growth inhibition after 72 hrs by MTT assay, IC50=1.811 μM
human A549 cells Proliferation assay 72 h Antiproliferative activity against k-RAS dependent human A549 cells overexpressing WT EGFR after 72 hrs by MTT assay, IC50=2.102 μM
human HL7702 cells Proliferation assay 72 h Antiproliferative activity against human HL7702 cells expressing wilt type EGFR after 72 hrs by MTS assay, IC50=2.73 μM
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Solubility

In vitro
Batch:

DMSO : 13 mg/mL (26.3 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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In vivo Formulation Calculator (Clear solution)

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Working concentration: mg/ml;

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Chemical Information, Storage & Stability

Molecular Weight 494.18 Formula

C25H27ClN6O3

 Storage (From the date of receipt)
CAS No. 1213269-23-8 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CN1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)OC4=CC=CC(=C4)NC(=O)C=C)Cl)OC

Mechanism of Action

Targets/IC50/Ki
EGFR (L858R)
(BaF3 cells)
2 nM
EGFR (L858R/T790M)
(BaF3 cells)
8 nM
In vitro
WZ4002 inhibits other EGFR genotypes E746_A750 and E746_A750/T790M with IC50 of 2 and 6 nM. Besides, this compound suppresses widetype ERBB2 with an IC50 of 32 nM. It inhibits EGFR, AKT and ERK1/2 phosphorylation in NSCLC cell lines and prevents of EGFR phosphorylation in NIH-3T3 cells expressing different EGFR T790M mutant alleles. For this chemical, kinases that exhibited greater than 95% inhibition relative to the DMSO control at 10 μM are selected for measurement of their dissociation constants. This inhibitor, which possesses an ortho-methoxy group at the C2-aniline substituent, is more selective for EGFR compared to WZ3146. It is 100-fold less effective at inhibiting phosphorylation of WT EGFR compared to the quinazoline inhibitors. Similarly, this compound 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. 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.
Kinase Assay
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.
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. Treatment with low-dose of this compound, and high-dose of this compound leads to mean decreases in tracer uptake of 26%, and 36%, respectively.
References

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