BMS 599626 2HCl

SKU: orb1301823

Description

BMS 599626 dihydrochloride (CAS 873837-23-1 (HCl)), also known as AC480 dihydrochloride, is a potent and selective ATP-competitive inhibitor of HER1/EGFR and HER2 tyrosine kinases, with IC50 values of 20 nM and 30 nM, respectively. It demonstrates significantly weaker activity against HER4 and many other kinases. This compound has been utilized in preclinical research to investigate HER-driven tumorigenesis in both cellular and animal models.

Research Area

Cardiovascular Research, Signal Transduction

Key Properties

• CAS Number: 1781932-33-9
• MW: 603.48
• Purity: 99.94% (May vary between batches)
• Formula: C₂₇H₂₉FN₈O₃Cl₂
• SMILES: O=C(OC[C@@H]1COCCN1)NC2=CN3C(C(NC4=CC=C(N(N=C5)CC6=CC(F)=CC=C6)C5=C4)=NC=N3)=C2C.Cl.Cl
• Target: HER
• Solubility: H2O:3 mg/mL (4.97 mM);DMSO:95 mg/mL (157.42 mM)

Bioactivity

• Target IC50:
  HER3:190 nM (cell free)|HER1:20 nM (cell free)|HER2:30 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 .
• 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 . At 10 μM, BMS-599626 did not exhibit significant off-target effects as reflected in its activity on the control A2780 tumor cells . 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 .
• 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 .
• 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 .

Storage & Handling

• Storage: Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

BMS 599626 2HCl (873837 23 1(HCl)), BMS 599626 2HCl (873837231(HCl)), BMS 599626 2HCl (873837-23-1(HCl)), AC 480, AC 480 Dihydrochloride, AC480, AC-480, AC480 Dihydrochloride, AC480 dihydrochloride, AC-480 Dihydrochloride, HER4, HER2, HER1

Compound Identifiers

PubChem CID

90488998