WZ4002 is a novel, selective EGFR kinase inhibitor against EGFR T790M (mutation of the gatekeeper T790 residue) with IC50 of 8 nM. This agent 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. 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. 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. In a 2-week efficacy study, WZ4002 treatment resulted in significant tumour regressions compared with vehicle alone in both T790M-containing murine models.
|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 ≥10 mg/mL|
|Source||Clin Cancer Res (2017). Figure 4. WZ4002 (Abmole Bioscience)|
|Cell Lines||Mice harboring H1975 ER-TWIST+4-OHT tumors|
|Incubation Time||5 d|
|Results||"Consistent with our in vitro observations, while single-agent WZ4002 was sufficient to markedly slow the growth of the tumors, the addition of ABT-263 was necessary to shrink tumors (Fig. 4D)."|
|Source||Clin Cancer Res (2017). Figure 3. WZ4002 (Abmole Bioscience)|
|Cell Lines||H1975 parental cells (par), H1975 R1 cells (R1), and H1975 R2 cells (R2)|
|Incubation Time||72 h|
|Results||Similarly, in the H1975 EMT model induced by ER-TWIST, knockdown of ZEB1 led to de-repression of BIM protein and RNA (Fig. 3I and Sup. Fig. 5B, right panel) and restored EGFRi-induced apoptosis and re-sensitized these EMT cancers to WZ4002 (Fig. 3J and 3K).|
|Source||Clin Cancer Res (2017). Figure 2. WZ4002 (Abmole Bioscience)|
|Cell Lines||HCC4006 and H1975 cells|
|Incubation Time||72 h|
|Results||We found directly inducing EMT by exogenous TWIST activation (Fig. 2) or chronic TGF- β treatment (Sup. Fig. 2) led to depressed levels of BIM resulting in suppression of EGFRi-induced apoptosis and resistance to EGFRi (WZ4002 and gefitinib).|
Clin Cancer Res. 2017 Oct 19; pii: clincanres.1577.2017.
Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM
WZ4002 purchased from AbMole
Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR mutant lung cancer.
Nakagawa et al. Mol Cancer Ther. 2012 Jul 25. PMID: 22844075.
NF-κB signaling is activated and confers resistance to apoptosis in three-dimensionally cultured EGFR-mutant lung adenocarcinoma cells.
Sakuma et al. Biochem Biophys Res Commun. 2012 Jul 13;423(4):667-71. PMID: 22695117.
WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors.
Sakuma et al. Lab Invest. 2012 Mar;92(3):371-83. PMID: 22157722.
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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