Afatinib, Free Base **

产品名称：Afatinib, Free Base
产品货号：LC  A-8644
产品规格：10 MG
Storage:  Store at or below -20 ºC.  Solubility:  Soluble in DMSO at 200 mg/mL; soluble in ethanol at 25 mg/mL; very poorly soluble in water; maximum solubility in plain water is estimated to be about 50-100 µM; buffers, serum, or other additives may increase or decrease the aqueous solubility.  Disposal:  A
Afatinib, also known as BIBW-2992, is an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinases.
Afatinib inhibits EGFR1 tyrosine kinase (IC50 = 0.5 nM) and EGFR2 (HER2) tyrosine kinase (IC50 = 14 nM).  It also suppresses EGF-induced EGFR phosphorylation and cellular proliferation in various cell lines, including EGFR-overexpressing and HER2-expressing cell lines A431, NIH-3T3-HER2, NCI-N87 and BT-474.  Oral afatinib induced tumor regression in mice carrying A431 or MDA-MB-453 xenografts.  Both xenografts are EGFR-overexpressing and HER2-expressing.  Afatinib also showed inhibitory effects in NCI-N87 gastric and SKOV-3 ovarian models.  Eskens, F.A., et al.  "A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours."  Br. J. Cancer 98:  80-85 (2008).
Afatinib inhibits the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms.  Afatinib suppressed proliferation of cancer cell lines and caused tumor regression in xenograft and transgenic lung cancer models, with activity superior to that of erlotinib.  Li, D., et al.  "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models."  Oncogene 27:  4702-4711 (2008).
Combination treatment of HER2(YVMA) transgenic mice or H1781 xenografts with afatinib and rapamycin caused significant tumor shrinkage and was an effective treatment paradigm in the adenosquamous lung tumor model in mice.  Perera, S.A., et al.  "HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy."  Proc. Natl. Acad. Sci. USA 106:  474-479 (2009).
The EGFR T854A mutation reduces the inhibition of tyrosine phosphorylation by erlotinib.  Afatinib overcomes the resistance.  Bean, J., et al.  "Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma."  Clin. Cancer Res. 14:  7519-7525 (2008).
Tumors overexpressing EGFR with the secondary T790M point mutation show resistance to the first-generation EGFR inhibitors gefitinib and erlotinib.  Such resistance is overcome by afatinib.  Minkovsky, N. and Berezov, A.  "BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors."  Curr. Opin. Investig. 9:  1336-1346 (2008).
Afatinib is the active ingredient in the drug product sold under the trade names Tovok® and Tomtovok®.  This drug is currently approved in at least one country for use in patients with non-small cell lung carcinoma.  NOTE:  THE AFATINIB, FREE BASE RESEARCH COMPOUND SOLD BY LC LABORATORIES IS NOT TOVOK® OR TOMTOVOK®, AND IS NOT FOR HUMAN USE.
Chemical Abstracts Service currently has two different CAS numbers for afatinib.  One of them, 439081-18-2, is by far the most widely used, but its entry in the CAS database does not show the geometry of the double bond.  A later CAS number, 850140-72-6, is not in wide use, but its entry in the CAS database shows the trans geometry of the double bond.  It is likely that CAS will eventually cancel one of these two numbers.
Related CAS numbers:  850140-73-7 for the afatinib dimaleate salt.
Another CAS number previously assigned to afatinib, namely 915958-11-1, has been deleted by CAS and is no longer in 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.

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