product name WZ4002
Description: WZ4002 is a novel, potent, and mutant-selective EGFR inhibitor for EGFR(L858R)/(T790M) with IC50 of 2 nM/8 nM in BaF3 cell line; it does not inhibit ERBB2 phosphorylation (T798I). EGFR T790M (mutation of the gatekeeper T790 residue) is detected in 50% of clinically resistant patients to gefitinib or erlotinib. WZ4002 has a basic chemical framework (covalent pyrimidine) which is different from that of other EGFR inhibitors.
References: Nature. 2009 Dec 24;462(7276):1070-4; J Nucl Med. 2012 Mar;53(3):443-50.
494.18
Formula
C25H27ClN6O3
CAS No.
1213269-23-8
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 13 mg/mL (26.3 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19416851
| In Vitro |
In vitro activity: 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. 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: 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: 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. |
|---|---|
| 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 WZ4002, and high-dose WZ4002 leads to mean decreases in tracer uptake of 26%, and 36%, respectively. |
| Animal model | EGFR-TL (T790M/L858R) mice |
| Formulation & Dosage | Dissolved in NMP (10% 1-methyl-2-pyrrolidinone: 90% PEG-300; 25 mg/kg; Oral gavage |
| References | Nature. 2009 Dec 24;462(7276):1070-4; J Nucl Med. 2012 Mar;53(3):443-50. |
