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Angiogenesis HER BMS 599626 2HCl (873837-23-1(HCl))

BMS 599626 2HCl (873837-23-1(HCl))

Catalog No. T5398   CAS T5398
Synonyms: AC480 dihydrochloride, AC480 dihydrochloride
Purity 99.94% Datasheet

BMS-599626 (AC480) is a selective inhibitor of HER1 and HER2 (IC50s: 20 nM and 30 nM), ~8-fold less potent to HER4, >100-fold to Lck, VEGFR2, c-Kit, MET, etc.

BMS 599626 2HCl (873837-23-1(HCl)), CAS T5398
Pack Size Availability Price/USD Quantity
1 mg In stock 50.00
5 mg In stock 126.00
25 mg In stock 419.00
50 mg In stock 672.00
1 mL * 10 mM (in DMSO) In stock 320.00
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Purity 99.94%
Biological Description
Chemical Properties
Storage & Solubility Information
Description BMS-599626 (AC480) is a selective inhibitor of HER1 and HER2 (IC50s: 20 nM and 30 nM), ~8-fold less potent to HER4, >100-fold to Lck, VEGFR2, c-Kit, MET, etc.
Targets&IC50 HER1 :ic50 20 nM (cell free),   HER2 :ic50 30 nM (cell free),   HER3 :ic50 190 nM (cell free),  
In vivo At 60 mg/kg, BMS-599626 achieved a significant delay of tumor growth in the course of treatment, but tumor growth resumed following the cessation of treatment. Higher doses of BMS-599626 provided more sustained inhibition of tumor growth, but in all cases, tumor growth resumed on treatment cessation. In a once-daily regimen, the maximum tolerated dose for 14 days of dosing of BMS-599626 was 240 mg/kg [1].
Kinase Assay The entire cytoplasmic sequences of HER1, HER2, and HER4 were expressed as recombinant proteins in Sf9 insect cells. HER1 and HER4 were expressed as fusion proteins with glutathione-S-transferase and were purified by affinity chromatography on glutathione-S-Sepharose. HER2 was subcloned into the pBlueBac4 vector and expressed as an untagged protein using an internal methionine codon for translation initiation. The truncated HER2 protein was isolated by chromatography on a column of DEAE-Sepharose equilibrated in a buffer that contained 0.1 mol/L NaCl, and the recombinant protein was eluted with a buffer containing 0.3 mol/L NaCl. For the HER kinase assays, reaction volumes were 50 μL and contained 10 ng of glutathione-S-transferase fusion protein or 150 ng of partially purified HER2. The mixtures also contained 1.5 μmol/L poly(Glu/Tyr) (4:1), 1 μmol/L ATP, 0.15 μCi [γ-33P]ATP, 50 mmol/L Tris-HCl (pH 7.7), 2 mmol/L DTT, 0.1 mg/mL bovine serum albumin, and 10 mmol/L MnCl2. Reactions were allowed to proceed at 27°C for 1 hour and were terminated by the addition of 10 μL of a stop buffer (2.5 mg/mL bovine serum albumin and 0.3 mol/L EDTA), followed by a 108-μL mixture of 3.5 mmol/L ATP and 5% trichloroacetic acid. Acid-insoluble proteins were recovered on GF/C Unifilter plates with a Filtermate harvester. Incorporation of radioactive phosphate into the poly(Glu/Tyr) substrate was determined by liquid scintillation counting. Percent inhibition of kinase activity was determined by nonlinear regression analyses and data were reported as the inhibitory concentration required to achieve 50% inhibition relative to control reactions (IC50). Data are the averages of triplicate determinations. All other tyrosine kinases were also assayed using poly(Glu/Tyr) as a substrate [1].
Cell Research
All cell lines were maintained in RPMI 1640 supplemented with 10% fetal bovine serum, 100 units/mL penicillin, and 100 μg/mL streptomycin. Cells were plated at 1,000 per well in 96-well plates and were cultured for 24 hours before test compounds were added. Compounds were diluted in culture medium such that the final concentration of DMSO never exceeded 1%. Following the addition of compounds, the cells were cultured for an additional 72 hours before cell viability was determined by measuring the conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye with the CellTiter96 kit. For some cell lines, there was a lack of a correlation between 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye metabolism and cell number, and a thymidine uptake assay was used to measure proliferation of these cell lines. Cells were plated in 96-well plates and treated with compounds as above. At the end of the 72-hour incubation, cells were pulsed with [3H]thymidine (0.4 μCi/well) for 3 hours before they were harvested. Cells were digested with 2.5% trypsin for 10 minutes at 37°C and were harvested by filtration using a Packard Filtermate Harvester and GF/C Unifilter plates. Incorporation of radioactive thymidine into nucleic acids was determined by liquid scintillation counting [1].
Synonyms AC480 dihydrochloride , AC480 dihydrochloride
Purity 99.94%
Molecular Weight 603.47
Formula C27H29Cl2FN8O3
CAS No. T5398

Storage

-20℃ 3 years powder

-80℃ 2 years in solvent

Solubility Information

DMSO: 95 mg/mL (167.55 mM)

Water: 3 mg/mL

( < 1 mg/ml refers to the product slightly soluble or insoluble )

Citations

References and Literature
1. Wong TW, et al. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6186-93. 2. Gavai AV, et al. Discovery and preclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selective and orally efficacious inhibitor of human epidermal growth factor receptor 1 and 2 kinases. J Med Chem. 2009 Nov 12;52(21):6527-30. 3. Torres MA, et al. AC480, formerly BMS-599626, a pan Her inhibitor, enhances radiosensitivity and radioresponse of head and neck squamous cell carcinoma cells in vitro and in vivo. Invest New Drugs. 2011 Aug;29(4):554-61.

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