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Afatinib (BIBW2992)Irreversible EGFR/HER2 inhibitor

Afatinib (BIBW2992)

Catalog No. A8247
Size Price Stock Qty
10mM (in 1mL DMSO) $168.00 In stock
Evaluation Sample $28.00 In stock
5mg $84.00 In stock
10mg $147.00 In stock
50mg $399.00 In stock

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Sample solution is provided at 25 µL, 10mM.

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Chemical structure

Afatinib(BIBW2992)

Related Biological Data

Afatinib(BIBW2992)

Related Biological Data

Afatinib(BIBW2992)

Biological Activity

Description Afatinib (BIBW2992) is an irreversible inhibitor of EGFR/HER2 for EGFR(wt), EGFR(L858R), EGFR(L858R/T790M) and HER2 with IC50 of 0.5 nM, 0.4 nM, 10 nM and 14 nM, respectively; 100-fold more active against Gefitinib-resistant L858R-T790M EGFR mutant.
Targets EGFRwt EGFRL858R EGFR L858R/T790M HER2    
IC50 0.5 nM 0.4 nM 10 nM 14 nM    

Protocol

Cell experiment: [1]

Cell lines

NCI-H1975 and BT474 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reaction Conditions

EC50: 92 nM for NCI-H1975 cells, 54 nM for BT474 cells; 96 hours

Applications

The effect of the inhibitor on cellular proliferation was tested in various assay formats including anchorage-dependent (BT474 cells grown on plastic; two-dimensional assays) and anchorage-independent (NCI-H1975 cells grown in soft agar; three-dimensional assays) assays. Afatinib dose-dependently inhibited cell proliferation and showed nanomolar activity. The EC50 values for NCI-H1975 and BT474 cells were 92 nM and 54 nM, respectively.

Animal experiment: [2]

Animal models

Transgenic mice expressing the delE748-A752 version of mouse Egfr and the L858R version of human EGFR

Dosage form

Oral administration, 5 mg/kg, once daily, 5 days per week

Applications

The transgenic mice received the oral administration of the drug until toxicity or death. All mice in the control group died, with a median survival time of 119 days. Afatinib treatment significantly enhanced the survival of transgenic mice with a median survival time of 456 days. No toxic death was observed in any mice. Four weeks after the initiation of treatment, body weight in the control group was significantly lower than in the afatinib group.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. Journal of Pharmacology and Experimental Therapeutics, 2012, 343(2): 342-350.

[2] Ninomiya T, Takigawa N, Ichihara E, et al. Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model. Molecular cancer therapeutics, 2013, 12(5): 589-597.

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Chemical Properties

Cas No. 439081-18-2 SDF Download SDF
Chemical Name (E)-N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide
Canonical SMILES CN(C)CC=CC(=O)NC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC(=C(C=C3)F)Cl)OC4CCOC4
Formula C24H25ClFN5O3 M.Wt 485.94
Solubility Soluble in DMSO > 10 mM Storage Store at -20°C
General tips No
Shipping Condition No

Background

Afatinib (BIBW2992), an irreversible inhibitor of the ErbB family of tyrosine kinases, downregulates ErbB signalling by binding to the kinase domains of epidermal growth factor receptor (EGFR)/ human epidermal growth factor receptor 2 (HER2) with IC50 of 0.5 nM and 14nM, respectively.
The ErbB receptor tyrosine kinase family consists of four cell surface receptors: ErbB1/ EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. It has been shown that EGFR and HER2 play important roles in the development and progression of certain aggressive types of cancers and inflammation-associated diseases.
Afatinib was shown to suppress EGF-induced phosphorylation of EGFR and cell proliferation in a variety of EGFR-overexpressing and HER2-expressing cell lines such as A431, NIH-3T3-HER2, NCI-N87 and BT-474 [1].
The component has also been used extensively in various animal models to study the role of EGFR/HER2. Oral administration of afatinib inhibited cancer cell growth and survival and suppress the tumor regression in xenograft and transgenic lung cancer models [2]. In addition, afatinib is identified as EGFR blocker which was approved for the treatment of patients with EGFR-mutated nonsmall cell lung cancer [3].
References:
1.Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H, 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 2008,98:80-85.
2.Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008,27:4702-4711.
3.Engle JA, Kolesar JM. Afatinib: A first-line treatment for selected patients with metastatic non-small-cell lung cancer. Am J Health Syst Pharm 2014,71:1933-1938.