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

Catalog No. T5398 CAS T5398

Synonyms: AC480 dihydrochloride

BMS 599626 2HCl (873837-23-1(HCl)) (AC480 dihydrochloride) 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.

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

BMS 599626 2HCl (873837-23-1(HCl)), CAS T5398

Pack Size	Availability	Price/USD
1 mg	In stock	$ 50.00
5 mg	In stock	$ 113.00
10 mg	In stock	$ 178.00
25 mg	In stock	$ 377.00
50 mg	In stock	$ 558.00
100 mg	In stock	$ 788.00
1 mL * 10 mM (in DMSO)	In stock	$ 288.00

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Purity: 99.94%

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Description	BMS 599626 2HCl (873837-23-1(HCl)) (AC480 dihydrochloride) 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	HER3:190 nM (cell free), HER1:20 nM (cell free), HER2:30 nM (cell free)
In vitro	BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 micromol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling [1]. At 10 μM, BMS-599626 did not exhibit significant off-target effects as reflected in its activity on the control A2780 tumor cells [2]. In HN-5 cells, BMS-599626 inhibited the expression of pEGFR, pHER2, cyclins D and E, pRb, pAkt, pMAPK, pCDK1 and 2, CDK 6, and Ku70 proteins. The drug also induced accumulation of cells in the G1 cell cycle phase, inhibited cell growth, enhanced radiosensitivity [3].
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].
Animal Research	The following murine and human tumor models were employed in the evaluation of BMS-599626: SAL2 murine salivary gland tumor, N87 human gastric carcinoma, BT474 human breast tumor, A549 human non–small-cell lung tumor, and GEO human colon tumor. All tumors were maintained and passaged in athymic female nude mice (nu/nu, HSD). Tumors were propagated as s.c. transplants using tumor fragments obtained from donor mice. For oral administration to mice, BMS-599626 was dissolved in a mixture of propylene glycol/water (50:50). The volume of all compounds administered was 0.01 mL/g body weight. Each nude mouse was given a s.c. implant of a tumor fragment (～20 mg) with a 13-gauge trocar. Tumors were allowed to grow to ～100 to 200 mm3 and animals were evenly distributed to various treatment and control groups of eight mice each. Tumor response was determined by measurement of tumors with a caliper twice a week until the tumors reached a predetermined "target" size of 0.5 to 1.0 g. Tumor weights (mg) were estimated from the following formula: tumor weight = (length × width2) / 2 [1].

Synonyms	AC480 dihydrochloride
Molecular Weight	603.47
Formula	C27H29Cl2FN8O3
CAS No.	T5398

Storage

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

Solubility Information

DMSO: 95 mg/mL (167.55 mM)

H2O: 3 mg/mL

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.

Related compound libraries

This product is contained In the following compound libraries：

Inhibitor Library Drug Repurposing Compound Library Anti-Cancer Active Compound Library Anti-Cancer Clinical Compound Library Anti-Cancer Drug Library Tyrosine Kinase Inhibitor Library Bioactive Compounds Library Max Reprogramming Compound Library Anti-Lung Cancer Compound Library Anti-Liver Cancer Compound Library

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Keywords

BMS 599626 2HCl (873837-23-1(HCl)) T5398 Angiogenesis JAK/STAT signaling Tyrosine Kinase/Adaptors HER BMS 599626 2HCl (873837 23 1(HCl)) AC480 Dihydrochloride AC 480 AC480 dihydrochloride AC 480 Dihydrochloride BMS 599626 2HCl (873837231(HCl)) AC-480 AC480 AC-480 Dihydrochloride inhibitor inhibit

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