Afatinib free base
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MedKoo CAT#: 200500

CAS#: 850140-72-6 (free base)

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.


Chemical Structure

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Afatinib free base
CAS# 850140-72-6 (free base)

Theoretical Analysis

MedKoo Cat#: 200500
Name: Afatinib free base
CAS#: 850140-72-6 (free base)
Chemical Formula: C24H25ClFN5O3
Exact Mass: 485.163
Molecular Weight: 485.94
Elemental Analysis: C, 59.32; H, 5.19; Cl, 7.30; F, 3.91; N, 14.41; O, 9.88

Price and Availability

Size Price Availability Quantity
100.0mg USD 90.0 Ready to ship
200.0mg USD 150.0 Ready to ship
500.0mg USD 250.0 Ready to ship
1.0g USD 450.0 Ready to ship
2.0g USD 850.0 Ready to ship
5.0g USD 1650.0 Ready to ship
10.0g USD 2650.0 Same Day
20.0g USD 3650.0 Same Day
50.0g USD 4650.0 2 Weeks
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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

Appearance: White to light yellow solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Afatinib (BIBW 2992) is an irreversible EGFR family inhibitor with IC50s of 0.5 nM, 0.4 nM, 10 nM and 14 nM for EGFRwt, EGFRL858R, EGFRL858R/T790M and HER2, respectively.
In vitro activity: To investigate the molecular mechanisms underlying afatinib function, the activity of ERK and the expression levels of VEGF and MMP9 were investigated following treatment with afatinib. RT-qPCR and western blot analysis results suggested that the expression levels of VEGF and MMP9 were decreased by afatinib through EGFR inhibition (Fig. 4A and B). Moreover, the phosphorylation level of ERK was significantly decreased after treatment with afatinib through EGFR inhibition, and the ratio of p-ERK/ERK was significantly decreased after treatment with afatinib through EGFR inhibition (Fig. 4C and D). The present results suggested that afatinib decreased the activity of the ERK-VEGF/MMP9 signaling pathway in vitro. Reference: Mol Med Rep. 2019 Oct; 20(4): 3317–3325. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755195/
In vivo activity: When this study analyzed the lungs of these mice, this study noticed significantly reduced tumor burden and number in lungs of afatinib treated mice as compared to vehicle treated mice (Fig. S7A and S7B). In accordance to reduced tumor area this study also detected reduced oncogenic K-ras G12D levels in total lung lysates of the afatinib treated group, which reflects the decreased amount of tumor cells in the lungs (Fig. S7C). Reference: Sci Transl Med. 2018 Jun 20; 10(446): eaao2301. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610658/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 98.5 202.7
Ethanol 97.0 199.61

Preparing Stock Solutions

The following data is based on the product molecular weight 485.94 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Chen Y, Chen X, Ding X, Wang Y. Afatinib, an EGFR inhibitor, decreases EMT and tumorigenesis of Huh‑7 cells by regulating the ERK‑VEGF/MMP9 signaling pathway. Mol Med Rep. 2019 Oct;20(4):3317-3325. doi: 10.3892/mmr.2019.10562. Epub 2019 Aug 6. PMID: 31432165; PMCID: PMC6755195. 2. Chen YJ, Hsu CC, Shiao YJ, Wang HT, Lo YL, Lin AMY. Anti-inflammatory effect of afatinib (an EGFR-TKI) on OGD-induced neuroinflammation. Sci Rep. 2019 Feb 21;9(1):2516. doi: 10.1038/s41598-019-38676-7. Erratum in: Sci Rep. 2021 Jan 25;11(1):2693. PMID: 30792526; PMCID: PMC6385176. 3. Liu Z, Chen Z, Wang J, Zhang M, Li Z, Wang S, Dong B, Zhang C, Gao J, Shen L. Mouse avatar models of esophageal squamous cell carcinoma proved the potential for EGFR-TKI afatinib and uncovered Src family kinases involved in acquired resistance. J Hematol Oncol. 2018 Aug 29;11(1):109. doi: 10.1186/s13045-018-0651-z. PMID: 30157900; PMCID: PMC6114252. 4. Moll HP, Pranz K, Musteanu M, Grabner B, Hruschka N, Mohrherr J, Aigner P, Stiedl P, Brcic L, Laszlo V, Schramek D, Moriggl R, Eferl R, Moldvay J, Dezso K, Lopez-Casas PP, Stoiber D, Hidalgo M, Penninger J, Sibilia M, Győrffy B, Barbacid M, Dome B, Popper H, Casanova E. Afatinib restrains K-RAS-driven lung tumorigenesis. Sci Transl Med. 2018 Jun 20;10(446):eaao2301. doi: 10.1126/scitranslmed.aao2301. PMID: 29925635; PMCID: PMC7610658.
In vitro protocol: 1. Chen Y, Chen X, Ding X, Wang Y. Afatinib, an EGFR inhibitor, decreases EMT and tumorigenesis of Huh‑7 cells by regulating the ERK‑VEGF/MMP9 signaling pathway. Mol Med Rep. 2019 Oct;20(4):3317-3325. doi: 10.3892/mmr.2019.10562. Epub 2019 Aug 6. PMID: 31432165; PMCID: PMC6755195. 2. Chen YJ, Hsu CC, Shiao YJ, Wang HT, Lo YL, Lin AMY. Anti-inflammatory effect of afatinib (an EGFR-TKI) on OGD-induced neuroinflammation. Sci Rep. 2019 Feb 21;9(1):2516. doi: 10.1038/s41598-019-38676-7. Erratum in: Sci Rep. 2021 Jan 25;11(1):2693. PMID: 30792526; PMCID: PMC6385176.
In vivo protocol: 1. Liu Z, Chen Z, Wang J, Zhang M, Li Z, Wang S, Dong B, Zhang C, Gao J, Shen L. Mouse avatar models of esophageal squamous cell carcinoma proved the potential for EGFR-TKI afatinib and uncovered Src family kinases involved in acquired resistance. J Hematol Oncol. 2018 Aug 29;11(1):109. doi: 10.1186/s13045-018-0651-z. PMID: 30157900; PMCID: PMC6114252. 2. Moll HP, Pranz K, Musteanu M, Grabner B, Hruschka N, Mohrherr J, Aigner P, Stiedl P, Brcic L, Laszlo V, Schramek D, Moriggl R, Eferl R, Moldvay J, Dezso K, Lopez-Casas PP, Stoiber D, Hidalgo M, Penninger J, Sibilia M, Győrffy B, Barbacid M, Dome B, Popper H, Casanova E. Afatinib restrains K-RAS-driven lung tumorigenesis. Sci Transl Med. 2018 Jun 20;10(446):eaao2301. doi: 10.1126/scitranslmed.aao2301. PMID: 29925635; PMCID: PMC7610658.

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 1: Belani CP. The role of irreversible EGFR inhibitors in the treatment of non-small cell lung cancer: overcoming resistance to reversible EGFR inhibitors. Cancer Invest. 2010 May;28(4):413-23. Review. PubMed PMID: 20307200.

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

3: Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 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 of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res. 2010 Feb 1;70(3):868-74. Epub 2010 Jan 26. PubMed PMID: 20103621.

5: Doebele RC, Oton AB, Peled N, Camidge DR, Bunn PA Jr. New strategies to overcome limitations of reversible EGFR tyrosine kinase inhibitor therapy in non-small cell lung cancer. Lung Cancer. 2010 Jan 19. [Epub ahead 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 drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest. 2009 Oct;119(10):3000-10. doi: 10.1172/JCI38746. Epub 2009 Sep 14. PubMed PMID: 19759520; PubMed Central PMCID: PMC2752070.

7: Ocaña A, Amir E. Irreversible pan-ErbB tyrosine kinase inhibitors and breast 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 epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer. 2009 Jul;10(4):281-9. Review. PubMed PMID: 19632948; PubMed Central 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 of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):474-9. Epub 2009 Jan 2. PubMed PMID: 19122144; PubMed Central PMCID: PMC2626727.

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



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.