WZ8040 is a novel EGFR inhibitor which suppresses the growth of EGFR-T790M-containing cell lines and inhibits EGFR phosphorylation. WZ8040 has a basic chemical framework (covalent pyrimidine) which is different from that of other EGFR inhibitors. WZ8040 is 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wildtype EGFR, than quinazoline-based EGFR inhibitors (HKI-272 and CL-387,785) in vitro.
|Cell lines||NSCLC or Ba/F3 cells|
|Preparation method||Cell proliferation and growth assays
NSCLC or Ba/F3 cells were exposed to treatment for 72 hours and the number of cells used per experiment determined empirically and has been previously established2,7. All experimental points were set up in six to twelve wells and all experiments were repeated at least three times. The data was graphically displayed using GraphPad Prism version 5.0 for Windows, (GraphPad Software; www.graphpad.com). The curves were fitted using a non-linear regression model with a sigmoidal dose response.
|Incubation time||72 h|
|Animal models||EGFR-TL (T790M/L858R) mice and EGFR exon19 Deletion-T790M (TD) inducible bitransgenic mice|
|Formulation||NMP (10% 1-methyl-2-pyrrolidinone: 90% PEG-300)|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥90 mg/mL|
|Source||Nature (2009). Figure 2. WZ8040|
|Cell Lines||3T3 cells|
|Incubation Time||16 h|
|Results||These compounds were 3- to 100-fold less potent, with WZ compounds being least potent, than CL-387,785 and HKI-272 at inhibiting the growth of the EGFR WT cells.|
|Source||Nature (2009). Figure 1. WZ8040|
|Cell Lines||PC9 GR cells|
|Incubation Time||16 h|
|Results||We observed a similar increased potency of the WZ compounds in the H1975 (L858R/T790M) cell line and in Ba/F3 cells harbouring EGFR T790M|
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.
Zhou W, et al. Nature. 2009 Dec 24;462(7276):1070-4. PMID: 20033049.
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