Gefitinib, Free Base (Iressa, ZD-1839, CAS 184475-35-2), >99%

LC Laboratories' Product Number G-4408 - Gefitinib, Free Base (Iressa, ZD-1839), >99% - for research use only. EGFR tyrosine kinase inhibitor that binds to the ATP-binding site of the enzyme. The functions of the EGFR tyrosine kinase in activating the Ras signal transduction cascade and malignant cell growth are thus inhibited. It has been shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways in gefitinib-sensitive non-small cell lung cancers. These mutations tend to increase sensitivity to tyrosine kinase inhibitors including gefitinib and erlotinib. The adenocarcinoma subset of non-small cell lung cancer histologies often have these mutations, which are commonly found in Asians, women, and non-smokers. The IC50 values for gefitinib for inhibiting HT-29 and LoVo cell growth were 23.6 - >100 µM and 7.3 - 48.5 µM, respectively, when the exposure times are from 18 hours to 3 days. A time-dependent reduction in IC50 was observed for gefitinib, with the IC50 after 3 days of exposure being 4-8 fold less after 18 hours of exposure. Gefitinib was found to be a potent inhibitor of EGFR kinase (Ki = 0.40 nM), but much weaker against ErbB-2 kinase (Ki = 870 nM) and ErbB-4 kinase (Ki = 1.1 µM). The IC50 of gefitinib for cells grown in the absence (IC50 = 8.8 µM) of EGF is >100-fold weaker than that in the presence (IC50 = 0.054 µM) of EGF.  Gefitinib selectively inhibited EGF-stimulated growth of HUVECs (IC50 = 0.03 - 0.1 µM) compared with FGF- or VEGF-stimulated growth (IC50 = 1 - 3 µM for both). Enzyme kinetic studies were used to determine the characteristics of gefitinib inhibition of EGFR tyrosine kinase.  Gefitinib is a competitive inhibitor with respect to ATP (Ki = 2.1 nM) when the peptide substrate concentration was fixed at 2 mM (6-fold higher than the Km) and the ATP concentration was varied.  Gefitinib showed noncompetitive kinetics (Ki = 15.0 nM) when the ATP concentration was 50 µM (6-fold higher than the Km) and the peptide concentration was varied. Gefitinib is the active ingredient in the drug sold under the trade name Iressa, which has been approved in at least one country for treatment of patients with locally advanced or metastatic non-small cell lung cancer who have previously received chemotherapy. While gefitinib, as of this writing, has yet to be shown to be effective in other cancers, there may be potential for its use to treat patients with other cancers where EGFR overexpression is involved.

• Supplier: LC Laboratories
• Product #: G-4408
• Sku #: G-4408_1g