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PD153035 (4-(3-Bromoanilino)-6,7-dimethoxyquinazoline) is an extremely potent epidermal growth factor receptor (EGFR) inhibitor that competitively binds at the ATP site with the half maximal inhibition concentration IC50 of 0.025 nM resulting in the inhibition of the tyrosine kinase activity of the EGFR [1].
PD153035 has been found to inhibit EGF-dependent EGFR phosphorylation in a variety of human cancer cell lines over-expressing EGFRs, which include A431, Difi, DU145, MDA-MB-468, ME180 and C4i, with IC50 of 0.22 μM, 0.3 μM, 0.4 μM, 0.68 μM, 0.95 μM and 2.5 μM respectively leading to suppression of proliferation and clonogenicity in those cell lines [2].
Besides exerting potent inhibition against EGFRs, PD153035 also inhibits the closely related HER2/neu receptor but to a lesser degree [2].
References:[1] Bridges AJ, Zhou H, Cody DR, Rewcastle GW, McMichael A, Showalter HD, Fry DW, Kraker AJ, Denny WA. Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J Med Chem. 1996 Jan 5;39(1):267-76.[2] Bos M, Mendelsohn J, Kim YM, Albanell J, Fry DW, Baselga J. PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res. 1997 Nov;3(11):2099-106.
Cell lines
A panel of cancer cell lines overexpressing various levels of EGF receptor and HER2/neu.
Preparation method
The solubility of this compound in DMSO is limited. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
Reacting condition
0.5-2800 nM; 2 h
Applications
In EGF receptor-overexpressing cell lines, PD153035 caused a dose-dependent decrease in ligand-inducedEGF receptor phosphorylation. PD153035 only inhibited HER2/neu phosphorylation at the highest concentrations tested (1400-2800 nM). PD153035 also inhibited cell proliferation in EGF receptor-positive cell lines.
Animal models
Immunodeficient nude mice xenografted with A431 human epidermoid tumors
Dosage form
i.p. dose of 80 mg/kg
Application
In immunodeficient nude mice xenografted with A431 human epidermoid tumors, PD153035 rapidly suppressed the tyrosine phosphorylation of the EGF receptor by 80-90% in the tumors. Following a single i.p. dose of 80 mg/kg, the drug levels in the plasma and tumor rose to 50 and 22 μM within 15 minutes.
Other notes
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References:
[1] Bos M, Mendelsohn J, Kim YM, Albanell J, Fry DW, Baselga J. PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res. 1997 Nov;3(11):2099-106.
[2]. Kunkel MW1, Hook KE, Howard CT, et al. Inhibition of the epidermal growth factor receptor tyrosine kinase by PD153035 in human A431 tumors in athymic nude mice. Invest New Drugs. 1996;13(4):295-302.
