AC480 (BMS-599626)

製品コードS1056 バッチS105601

化学情報

	Synonyms	N/A	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₂₇H₂₇FN₈O₃
	分子量	530.55	CAS No.	714971-09-2
Solubility (25°C)*	体外	DMSO	113 mg/mL (212.98 mM)
		Ethanol	20 mg/mL (37.69 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * 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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	AC480 (BMS-599626) is a selective and efficacious inhibitor of HER1 and HER2 with IC50 of 20 nM and 30 nM, ~8-fold less potent to HER4, >100-fold to VEGFR2, c-Kit, Lck, MET etc. Phase 1.
in vitro	BMS-599626 also inhibits the related receptor HER4, but with reduced potency with IC50 of 190 nM. BMS-599626 is identified as an ATP-competitive inhibitor for HER1 and as an ATP-noncompetitive inhibitor for HER2 with K_i of 2 nM and 5 nM, respectively. BMS-599626 inhibits the proliferation of tumor cells expressing high levels of HER1 and/or HER2, including Sal2, BT474, N87, KPL-4, HCC202, HCC1954, HCC1419, AU565, ZR-75-30, MDA-MB-175, GEO, and PC9 cells with IC50 of 0.24 μM, 0.31 μM, 0.45 μM, 0.38μM, 0.94 μM, 0.34 μM, 0.75 μM, 0.63 μM, 0.51 μM, 0.84 μM, 0.90 μM and 0.34 μM, respectively. While the proliferation of the ovarian tumor cell line A2780 and MRC5 fibroblasts, neither of which expresses HER1 or HER2, are not inhibited significant by BMS-599626. ^[1] A recent study shows that BMS-599626 significantly enhances the radiosensitivity of HN-5 cells expressing both EGFR and Her2 cell, by promoting cycle redistribution and inhibiting DNA repair. ^[2]
in vivo	In vivo, oral administration of BMS-599626 results in a dose-dependent inhibition of Sal2 tumor growth at doses ranging from 60 mg/kg to 240 mg/kg, yielding a potent antitumor activity in a human breast tumor KPL-4 xenograft at its maximum tolerated dose of 180 mg/kg, and also has similar antitumor activity in other HER2 amplified xenograft models, as well as other HER1-overexpressing xenograft models. ^[1]

プロトコル(参考用のみ)

キナーゼアッセイ	Protein kinase assays
キナーゼアッセイ	The entire cytoplasmic sequences of HER1, HER2, and HER4 are expressed as recombinant proteins in Sf9 insect cells. HER1 and HER4 are expressed as fusion proteins with glutathione-S-transferase and are purified by affinity chromatography on glutathione-S-Sepharose. HER2 is subcloned into the pBlueBac4 vector and expressed as an untagged protein using an internal methionine codon (M687) for translation initiation. The truncated HER2 protein is isolated by chromatography on a column of DEAE-Sepharose equilibrated in a buffer that contains 0.1 M NaCl, and the recombinant protein is eluted with a buffer containing 0.3 M NaCl. For the HER kinase assays, reaction volumes are 50 μL and contains 10 ng of glutathione-S-transferase fusion protein or 150 ng of partially purified HER2. The mixtures also contains 1.5 μM poly(Glu/Tyr) (4:1), 1 μM ATP, 0.15 μCi [γ-³³P]ATP, 50 mM Tris-HCl (pH 7.7), 2 mM DTT, 0.1 mg/mL bovine serum albumin, and 10 mM MnCl₂. Reactions are allowed to proceed at 27°C for 1 hour and are terminated by the addition of 10 μL of a stop buffer (2.5 mg/mL bovine serum albumin and 0.3 M EDTA), followed by a 108-μL mixture of 3.5 mM ATP and 5% trichloroacetic acid. Acid-insoluble proteins are recovered on GF/C Unifilter plates with a Filtermate harvester. Incorporation of radioactive phosphate into the poly(Glu/Tyr) substrate is determined by liquid scintillation counting. Percent inhibition of kinase activity is determined by nonlinear regression analyses and data are 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 are also assayed using poly(Glu/Tyr) as a substrate. Kinetics of HER1 and HER2 inhibition are determined in reaction mixtures that contains varying concentrations of ATP and BMS-599626.
細胞アッセイ	細胞株	Sal2, BT474, N87, KPL-4, HCC202, HCC1954, HCC1419, AU565, ZR-75-30, MDA-MB-175, GEO, PC9, A2780 and MRC5
	濃度	0-10 μM
	反応時間	72 hours
	実験の流れ	All cell lines are maintained in RPMI 1640 supplemented with 10% fetal bovine serum, 100 units/mL penicillin, and 100 μg/mL streptomycin. Cells are plated at 1,000 per well in 96-well plates and are cultured for 24 hours before BMS-599626 is added. BMS-599626 is diluted in culture medium such that the final concentrations of DMSO are ≤ 1%. Following the addition of BMS-599626, the cells are cultured for an additional 72 hours before cell viability is 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 is 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 is used to measure proliferation of these cell lines. Cells are plated in 96-well plates and treated with compounds as above. At the end of the 72-hour incubation, cells are pulsed with [₃H]thymidine (0.4 μCi/well) for 3 hours before they are harvested. Cells are digested with 2.5% trypsin for 10 minutes at 37 °C and are harvested by filtration using a Packard Filtermate Harvester and GF/C Unifilter plates. Incorporation of radioactive thymidine into nucleic acids is determined by liquid scintillation counting.
動物実験	動物モデル	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 are maintained and passaged in athymic female nude mice.
	投薬量	≤240 mg/kg
	投与方法	Administered via p.o.

参考

カスタマーフィードバック

: Data from [J Cell Mol Med, 2013, 17(5), 648-56]

: Data from [Cancer Cell, 2012, 22(5), 656-667 ]

: , 2010, Dr. Zhang of Tianjin Medical University

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Deciphering the Role and Signaling Pathways of PKCα in Luminal A Breast Cancer Cells [ Int J Mol Sci, 2022, 23(22)14023]	PubMed: 36430510
Comprehensive pharmacogenomic characterization of gastric cancer. [ Genome Med, 2020, 18;12(1):17]	PubMed: 32070411
The AXL receptor tyrosine kinase is associated with adverse prognosis and distant metastasis in esophageal squamous cell carcinoma. [Hsieh MS, et al. Oncotarget, 2016, 7(24):36956-36970]	PubMed: 27172793
Gain- and Loss-of-Function Mutations in the Breast Cancer Gene GATA3 Result in Differential Drug Sensitivity [ PLoS Genet, 2016, 12(9):e1006279]	PubMed: 27588951
PlncRNA-1 induces apoptosis through the Her-2 pathway in prostate cancer cells. [Yang Q, et al. Asian J Androl, 2016, 10.4103/1008-682X]	PubMed: 27232851
[ Oncotarget, 2015, ]	PubMed: 25965827
Synergistic apoptosis in head and neck squamous cell carcinoma cells by co-inhibition of insulin-like growth factor-1 receptor signaling and compensatory signaling pathways [Axelrod MJ, et al. Head Neck, 2014, 10.1002/hed.23822.?]	PubMed: 24986420
CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models [Witkiewicz AK, et al. Genes Cancer, 2014, 5(7-8):261-72]	PubMed: 25221644
Inhibition of the PI3K/AKT pathway potentiates cytotoxicity of EGFR kinase inhibitors in triple-negative breast cancer cells. [Yi YW, et al. J Cell Mol Med, 2013, 17(5):648-56]	PubMed: 23601074
Crosstalk between ROR1 and the Pre-B Cell Receptor Promotes Survival of t (1; 19) Acute Lymphoblastic Leukemia. [Bicocca VT, et al. Cancer Cell, 2012, 22(5):656-67]	PubMed: 23153538

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人間や獣医の診断であるか治療的な使用のためにでない。

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