Afatinib (BIBW2992) Dimaleate
Molecular Weight(MW): 717.18
Afatinib (BIBW2992) Dimaleate irreversibly inhibits EGFR/HER2 including 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.
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|Description||Afatinib (BIBW2992) Dimaleate irreversibly inhibits EGFR/HER2 including 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.|
BIBW2992 is more effective than erlotinib, geﬁtinib, or lapatinib in inhibiting survival of lung cancer cell lines harboring wild-type (H1666) or L858R/T790M (NCI-H1975) EGFR. BIBW2992 is similarly effective against NSCLC lines expressing HER2 776insV (NCI-H1781) or EGFR E746_A750del (HCC827), but shows no activity toward A549 cells, which express wild-type EGFR and HER2. Afatinib enhances cytotoxicity of topotecan and mitoxantrone to SP cells, and increases the apoptosis induced by topotecan and mitoxantrone in SP cells.
|In vivo||In the MDA-MB-453 xenograft model, BIBW2992 (20 mg/kg, p.o.) results in dramatic tumor regression with a cumulative treated/control tumor volume ratio (T/C ratio) of 2%, and downregulation of EGFR and AKT phosphorylation. In A7, A431, FaDu, UT-SCC-14 and UT-SCC-15 xenograft models, application of BIBW 2992 (30 mg/kg, p.o.) leads to a significant prolongation of tumour growth time. In HER2-amplified xenograft medel, Afatinib (30 mg/kg, p.o.) results a markedly inhibition in tumor growth and a significant improvement in the duration of overall survival. In HER2-positive gastric cancer NCI-N87 xenograft, afatinib (25 mg/kg, p.o.) leads to dramatic tumor volume regression within 4 d and near-complete tumor resolution after 21 d of treatment.|
In vitro kinase activity assay:EGFR kinase: Each 100 µL enzyme reaction contained 10 μL of inhibitor in 50% Me2SO, 20 μL of substrate solution (200 mM HEPES pH 7.4, 50 mM Mg-acetate, 2.5 mg/mL poly (EY), 5 μg/mL bio-pEY) and 20 µL enzyme preparation. The enzymatic reaction is started by addition of 50 µL of a 100 µM ATP solution made in 10 mM MgCl2. Assays are carried out at room temperature for 30 min and terminated by the addition of 50 µL of stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 µL are transferred to a streptavidin coated microtiterplate, after an incubation time of 60 min at room temperature the plate is washed with 200 µL of wash solution (50 mM Tris, 0.05% Tween20). A 100 µL aliquot of a HRPO- labeled anti-PY antibody (PY20H Anti-Ptyr:HRP ) 250 ng/mL are added to the wells. After 60 min of incubation, the plate is washed three times with a 200 µL wash solution. The samples are then developed with a 100µL TMB Peroxidase Solution (A:B= 1:1). The reaction is stopped after 10 min. The plate is transferred to an ELISA reader and extinction is measured at OD450nm. HER2-IC enzyme: Enzyme activity is assayed in the presence or absence of serial inhibitor dilutions performed in 50 % Me2SO. Each 100 µL reaction contains similar components as described for EGFR kinase assay with addition of 1000 µM Na3VO4. The enzymatic reaction is started by addition of 50µL of 500 µM ATP solution made in 10 mM Mg-acetate. The dilution of the enzyme is set so that incorporation of phosphate into bio-pEY is linear with respect to time and amount of enzyme. The enzyme preparation is diluted in 20 mM HEPES pH 7.4, 130 mM NaCl, 0.05% Triton X-100, 1 mM DTT and 10% glycerol. Assays are carried out at room temperature for 30 min and terminated by the addition of 50 µL of stop solution. Src kinase assays: Each 100 µL reaction contained 10 µL of inhibitor in 50 % Me2SO, 20µL of enzyme preparation, 20 µL of substrate solution supplemented with 1000 µM Na3VO4. The enzymatic reaction is started by addition of 50 µL of a 1000 µM ATP solution made in 10 mM Mg-acetate. BIRK kinase assay: 250 mM Tris pH 7.4, 10mM DTT, 2.5 mg/mL poly(EY), 5 mg/mL bio-pEY is used as substrate solution and enzymatic reaction is started by addition of 50 µL of a 2 mM ATP solution made in 8 mM MnCl2, 20 mM Mg-acetate. VEGF2 and HGFR kinase assays: Assays are carried out at room temperature for 20 minutes and terminated by the addition of 10 µL of 5 % H3PO4. The precipitate is then trapped onto GF/B filters using a 96 well filter mate universal harvester. After extensive washing the filter plate is dried for 1 h at 50°C, sealed and incorporated radioactivity is determined by scintillation counting using a TopCount™ or a Microbeta b counter™.
|In vitro||DMSO||100 mg/mL (139.43 mM)|
|In vivo||Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
5% DMSO+30% PEG 300+ddH2O
For best results, use promptly after mixing.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT03711422||Not yet recruiting||Drug: Afatinib||Non-small Cell Lung Cancer|Leptomeningeal Disease|Central Nervous System Metastases||National Cancer Centre Singapore||October 2018||Phase 1|
|NCT03083678||Recruiting||Drug: Afatinib||Chordoma||Leiden University Medical Center|Chordoma Foundation|Boehringer Ingelheim||June 21 2018||Phase 2|
|NCT03370770||Active not recruiting||Drug: Afatinib|Drug: Osimertinib||Carcinoma Non-Small-Cell Lung||Boehringer Ingelheim||December 28 2017||--|
|NCT02423525||Recruiting||Drug: Afatinib||Brain Cancer||Santosh Kesari|Boehringer Ingelheim|John Wayne Cancer Institute||December 2016||Phase 1|
|NCT02695290||Terminated||Drug: Afatinib||Carcinoma Non-Small-Cell Lung|ErbB Receptors||Boehringer Ingelheim||March 17 2016||Phase 4|
|NCT02440854||Recruiting||--||Carcinoma Non-Small-Cell Lung||Boehringer Ingelheim||February 16 2016||--|
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