Afatinib free base

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WARNING: This product is for research use only, not for human or veterinary use.

Description:Afatinib, also know as BIBW 2992, is an orally bioavailable dual receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. EGFR/HER2 tyrosine kinase inhibitor BIBW 2992 irreversibly binds to and inhibits human epidermal growth factor receptors 1 and 2 (EGFR-1; HER2), which may result in the inhibition of tumor growth and angiogenesis. EGFR/HER2 are RTKs that belong to the EGFR superfamily; both play major roles in tumor cell proliferation and tumor vascularization and are overexpressed in many cancer cell types. Afatinib is approved in much of the world (including the United States, Canada, the United Kingdom and Australia) for the treatment of metastatic non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim. It acts as an angiokinase inhibitor.

Price and Availability

Afatinib free base, purity > 98%, is in stock. The same day shipping out after order is received.

Chemical Structure

Theoretical Analysis

MedKoo Cat#: 200500Name: Afatinib free baseCAS#: 850140-72-6 (free base)Chemical Formula: C24H25ClFN5O3Exact Mass: 485.163Molecular Weight: 485.94Elemental Analysis: C, 59.32; H, 5.19; Cl, 7.30; F, 3.91; N, 14.41; O, 9.88

Related CAS #:850140-73-7 (dimaleate)439081-18-2 (free base)850140-72-6 (free base)

Synonym:BIBW-2992; BIBW 2992; BIBW2992. Afatinib free base; trade name: Gilotrif, Tomtovok and Tovok.

IUPAC/Chemical Name:(S,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide.

InChi Key:ULXXDDBFHOBEHA-CWDCEQMOSA-N

InChi Code:InChI=1S/C24H25ClFN5O3/c1-31(2)8-3-4-23(32)30-21-11-17-20(12-22(21)34-16-7-9-33-13-16)27-14-28-24(17)29-15-5-6-19(26)18(25)10-15/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29)/b4-3+/t16-/m0/s1

SMILES Code:O=C(NC1=CC2=C(NC3=CC=C(F)C(Cl)=C3)N=CN=C2C=C1O[C@@H]4COCC4)/C=C/CN(C)C

Technical Data

Additional Information

Related: 439081-18-2(Afatinib free base);850140-73-7 (Afatinib dimaleate)

As of July 2012, it is undergoing Phase III clinical trials for this indication and breast cancer, as well as Phase II trials for prostate  and head and neck cancer,  and a Phase I glioma trial.  Afatinib is not a first-line treatment; it is only used after other therapies have failed. In October 2010 a Phase III trial in NSCLC patients called Lux-Lung 5 began with this drug. Fall 2010 interim results suggested the drug extended progression-free survival threefold compared to placebo, but did not extend overall survival.  In May 2012, the Phase IIb/III trial Lux-Lung 1 came to the same conclusion. Phase II results for breast cancer that over-expresses the protein human epidermal growth factor receptor 2 (Her2-positive breast cancer) were described as promising by the authors, with 19 of 41 patients achieving benefit from afatinib. Double-blind Phase III trials are under way to confirm or refute this finding. Her2-negative breast cancers showed limited or no response to the drug.   

References

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2: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find ExpClin Pharmacol. 2009 Dec;31(10):661-700. PubMed PMID: 20140276.

3: Gazdar AF. Epidermal growth factor receptor inhibition in lungcancer: the evolving role of individualized therapy. Cancer MetastasisRev. 2010 Mar;29(1):37-48. Review. PubMed PMID: 20127143.

4: Sos ML, Rode HB, Heynck S, Peifer M, Fischer F, Klüter S, Pawar VG,Reuter C, Heuckmann JM, Weiss J, Ruddigkeit L, Rabiller M, Koker M,Simard JR, Getlik M, Yuza Y, Chen TH, Greulich H, Thomas RK, Rauh D.Chemogenomic profiling provides insights into the limited activity ofirreversible EGFR Inhibitors in tumor cells expressing the T790M EGFRresistance mutation. Cancer Res. 2010 Feb 1;70(3):868-74. Epub 2010 Jan26. PubMed PMID: 20103621.

5: Doebele RC, Oton AB, Peled N, Camidge DR, Bunn PA Jr. New strategiesto overcome limitations of reversible EGFR tyrosine kinase inhibitortherapy in non-small cell lung cancer. Lung Cancer. 2010 Jan 19. [Epubahead of print] PubMed PMID: 20092908.

6: Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A,Koutcher JA, Spassova M, Ouerfelli O, Mellinghoff IK, Zakowski MF,Politi KA, Pao W. Dual targeting of EGFR can overcome a major drugresistance mutation in mouse models of EGFR mutant lung cancer. J ClinInvest. 2009 Oct;119(10):3000-10. doi: 10.1172/JCI38746. Epub 2009 Sep14. PubMed PMID: 19759520; PubMed Central PMCID: PMC2752070.

7: Ocaña A, Amir E. Irreversible pan-ErbB tyrosine kinase inhibitors andbreast cancer: current status and future directions. Cancer Treat Rev.2009 Dec;35(8):685-91. Epub 2009 Sep 4. Review. PubMed PMID: 19733440.

8: Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermalgrowth factor receptor tyrosine kinase inhibitors in non-small-cell lungcancers dependent on the epidermal growth factor receptor pathway. ClinLung Cancer. 2009 Jul;10(4):281-9. Review. PubMed PMID: 19632948; PubMedCentral PMCID: PMC2758558.

9: Perera SA, Li D, Shimamura T, Raso MG, Ji H, Chen L, Borgman CL,Zaghlul S, Brandstetter KA, Kubo S, Takahashi M, Chirieac LR, Padera RF,Bronson RT, Shapiro GI, Greulich H, Meyerson M, Guertler U, Chesa PG,Solca F, Wistuba II, Wong KK. HER2YVMA drives rapid development ofadenosquamous lung tumors in mice that are sensitive to BIBW2992 andrapamycin combination therapy. Proc Natl Acad Sci U S A. 2009 Jan13;106(2):474-9. Epub 2009 Jan 2. PubMed PMID: 19122144; PubMed CentralPMCID: PMC2626727.

10: Minkovsky N, Berezov A. BIBW-2992, a dual receptor tyrosine kinaseinhibitor for the treatment of solid tumors. Curr Opin Investig Drugs.2008 Dec;9(12):1336-46. Review. PubMed PMID: 19037840.