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G-4408 Gefitinib, Free Base, >99%

[ZD-1839] [Iressa]

M.W. 446.90

C22H24ClFN4O3

[184475-35-2]

M.I. 14:  4379

Storage:  Store at or below -20 ºC.  Solubility:  Soluble in DMSO, up to about 100 mg/mL; very poorly soluble in water or ethanol.  Disposal:  A

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• 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.  Pao, W., et al.  "EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib."  Proc. Natl. Acad. Sci. USA 101:  13306-13311 (2004).  Sordella, R., et al. "Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways."  Science 305:  1163-1167 (2004).

• 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.  Azzariti, A., et al.  "Prolonged exposure of colon cancer cells to the epidermal growth factor receptor inhibitor gefitinib (Iressa™) and to the antiangiogenic agent ZD6474:  Cytotoxic and biomolecular effects."  World J. Gastroenterol. 12:  5140-5147 (2006).

• 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).  Wood, E.R., et al. "A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib), Relationships among Protein Conformation, Inhibitor Off-Rate, and Receptor Activity in Tumor Cells."  Cancer Res. 64:  6652-6659 (2004).

• 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.  Wakeling, A.E., et al.  "ZD1839 (Iressa), An Orally Active Inhibitor of Epidermal Growth Factor Signaling with Potential for Cancer Therapy."  Cancer Res. 62:  5749-5754 (2002).

• 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.  NOTE:  The gefitinib sold by LC Laboratories is NOT Iressa®, and is NOT for human use.

• Sold for laboratory or manufacturing purposes only; not for human, veterinary, food, or household use.

• This product is offered for R&D use in accordance with (i) 35 USC 271(e)+A13(1) in the U.S.; (ii) Section 69.1 of Japanese Patent Law in Japan; (iii) Section 11, No. 2 of the German Patent Act of 1981 in Germany; (iv) Section 60, Paragraph 5b of the U.K. Patents Act of 1977 in the U.K.; (v) Sections 55.2(1) and 55.2(6) and other common law exemptions of Canadian patent law; (vi) Section 68B of the Patents Act of 1953 in New Zealand together with the amendment of same by the Statutes Amendment Bill of 2002; (vii) such related legislation and/or case law as may be or become applicable in the aforementioned countries; and (viii) such similar laws and rules as may apply in various other countries.

• Not available in some countries; not available to some institutions; not available for some uses.