WZ4002 is a novel, mutant selective EGFR inhibitor. The IC50 is 2 nM/8 nM when it acts on IC50 of 2 nM/8 nM in EGFR (L858R)/(T790M), and it has no inhibitory effect on ERBB2 phosphorylation (T798I).
WZ4002 also inhibit other EGFR genotypes. For instance, the IC50 is 2nM and 6nM respectively when it acts on E746_A750 and E746_A750/T790M. Besides, the IC50 is 32nM when it acts on wild-type EGFR. It could inhibit the phosphorylation of EGFR, AKT and ERK1/2 when it acts on non-small cell lung cancer (NSCLC). WZ4002 also could inhibit the phosphorylation of EGFR when it acts on NIH-3T3 cells expressing different EGFRT790M mutant alleles. The dissociation constant of kinase was 95% higher when in the test when WZ4002 involved than that in the test DMSO involved instead. Because in aniline substitution in the C2 WZ4002 could obtain a methoxy group when it acts on EGFR, thus it’s more effective when it acts on EGFR than WZ3146. Compared with the quinazoline inhibitors, the efficiency of WZ4002 is 100 times lower than when it acts on wild-type EGFR. The inhibitory effect of WZ4002 on EGFR kinase activity of recombinant L858R/T790M protein is much higher than restrainable wild-type EGFR’s. However HKI-272 and Gefitinib are happened to have opposite inhibitory effect compared with WZ4002. In addition, phosphorylation of EGFR in H1975 and HCC827 cells of anti-Src TKI could be completely inhibited by third-generation EGFR TKI and WZ4002.
When treated with T790M mutant mouse model for 2 weeks and had been used to study the efficacy of WZ4002, it is found that treatment with WZ4002 resulted in more effective significant tumor regression compared to the control group. When treated with low dose WZ4002 and high dose WZ4002, it would resulted in a 26% and 36% decrease in average uptake respectively.
WZ 4002 is an EGFR phosphorylation inhibitor.
A novel mutant-selective EGFR kinase inhibitor of EGFRL858R and EGFRL858R/T790M with IC50s of 2 nM and 8 nM, respectively.
ChEBI: WZ4002 is a pyrimidine compound having a 2-methoxy-4-(4-methylpiperazin-1-yl)anilino group at the 2-position, a 3-(acryloylamino)phenoxy group at the 4-position, and a chloro substituent at the 5-position. It has a role as a tyrosine kinase inhibitor and an antineoplastic agent. It is a member of pyrimidines, a member of piperazines and an organochlorine compound.
wz4002 is a novel mutant-selective epidermal growth factor receptor (egfr) kinase inhibitor that potently and irreversibly suppresses the atp-dependent auto-phosphorylation of both wild-type egfr and egfr mutants, including egfr dele746_a750/t790m, egfr l858r/t790m, egfr t790m, egfr dele746_a750 and egfr l858r, with inhibition constant ki of 13.6 nm, 1.8 nm, 4 nm, 5 nm, 3.9 nm and 8.5 nm respectively. although wz4002 is actively against egfr mutants rather than wild-type egfr at lower concentrations resulting in less toxicity in normal tissues, wild-type egfr is susceptible to higher concentrations of wz4002 as well as prolonged administration of wz4002, especially in tissues where it accumulates.
GENERAL STEPS: Acryloyl chloride (60 μL, 0.68 mmol) was slowly added dropwise at 0°C to a solution containing 4-(3-aminophenoxy)-5-chloro-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (300 mg, 0.68 mmol) and diisopropylethylamine (120 μL, 0.68 mmol) in a in a solution of dichloromethane (10 mL). The reaction mixture was kept stirred at 0°C for 2 hours. Upon completion of the reaction, the reaction was terminated by adding water (10 mL) and extracted three times with dichloromethane (3 x 6 mL). The organic phases were combined, dried over anhydrous sodium sulfate and subsequently concentrated under reduced pressure to give a pale white solid crude product. The crude product was purified by fast column chromatography using a solvent mixture of dichloromethane and methanol (98:2, v/v) to afford finally N-(3-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)acrylamide (white solid) in 31-36% yield.
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