| 名稱(chēng) | BMS-754807 |
| 描述 | Dual IGF-1R/InsR Inhibitor BMS-754807 is an oral small molecule inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (InsR) tyrosine kinases with potential antineoplastic activity. |
| 細(xì)胞實(shí)驗(yàn) | Cells are grown at their optimal density in RPMI +GlutaMax supplemented with 10% heat-inactivated fetal bovine serum (FBS), 10 mM Hepes, penicillin, and streptomycin. Cell proliferation is evaluated by incorporation of 3H-thymidine into DNA after exposure of cells to BMS-754807 for 72 hours. Results are expressed as an IC50, which is the drug concentration required to inhibit cell proliferation by 50% compared with untreated control cells.(Only for Reference) |
| 激酶實(shí)驗(yàn) | Kinase inhibition assays: The primary screen for BMS-754807 is an in vitro kinase assay using recombinant human IGF-1 receptor enzyme in biochemical assays using synthetic peptide KKSRGDYMTMQIG as a phosphoacceptor substrate. The selectivity profile is evaluated against multiple recombinant enzymes that are generated at BMS or purchased externally. The enzymatic assays are performed in Ubottom 384-well plates using a 30 μL reaction volume in assay buffer (100 mM Hepes pH 7.4, 10 mM MgCl2, 0.015% Brij35 and 4 mM DTT). The 60 minute reactions are initiated by combining ATP (concentration equivalent to Km ATP), 1.5 μM fluoresceinlabeled peptide substrate, enzyme and BMS-754807. The reactions are terminated with EDTA. The reaction mixtures are analyzed on the Caliper LabChip 3000 by electrophoretic separation of the fluorescent substrate and phosphorylated product. Inhibition data are calculated by comparison to enzyme-free control reactions for 100% inhibition and vehicle-only reactions for 0% inhibition. Compounds are dissolved in dimethylsulfoxide (DMSO, 10 mM stock) and evaluated at eleven concentrations. IC50 values are derived by non-linear regression analysis of the dose response curves. |
| 體外活性 | MS-754807（6.25 mg/kg）在轉(zhuǎn)基因衍生的IGF-Sal腫瘤小鼠模型中實(shí)現(xiàn)完全的腫瘤生長(zhǎng)抑制,同時(shí)抑制相關(guān)的pIGF-1R和pAKT.在具有IGF-1R-Sal腫瘤的裸鼠中,BMS-754807（12.5 mg/kg,口服）抑制腫瘤和血清中的IGF-1R磷酸化.25 mg/kg BMS-754807作用于攜帶KT-5 (Wilms),KT-14 (rhabdoid),Rh28 (rhabdomyosarcoma)和 OS-1移植瘤的小鼠模型,對(duì)腫瘤有明顯抑制作用.BMS-754807作用于一組選定的上皮(IGF-1R-Sal,GEO和Colo205）,造血（JJN3）和間質(zhì)（RD1和Rh41）移植瘤模型,抑制腫瘤生長(zhǎng),腫瘤生長(zhǎng)抑制率從53％至115％不等. |
| 體內(nèi)活性 | BMS-754807以13 nM,6 nM和21 nM的IC 50抑制IGF-1R-Sal細(xì)胞,Rh41和Geo中的IGF-1R的磷酸化。BMS-754807抑制IGF-1R-Sal細(xì)胞,Rh41和Geo中Akt的磷酸化,IC5??0為22 nM,13 nM和16 nM。BMS-754807誘導(dǎo)Rh41細(xì)胞凋亡。BMS-754807作用于IGF-Sal 細(xì)胞系,抑制IGF-1R (IC50 = 13 nM),下游靶點(diǎn)Akt (IC50 = 22 nM) 和MAPK(IC50 = 13 nM) 的磷酸化。在兒科臨床前期試驗(yàn)計(jì)劃（PPTP）中,BMS-754807作用于23種細(xì)胞系,平均EC50值為0.62 μM。包括間葉細(xì)胞（尤因氏,橫紋肌肉瘤,成神經(jīng)細(xì)胞瘤和脂肪肉瘤）,上皮細(xì)胞（乳腺癌,肺癌,胰腺癌,結(jié)腸癌和胃癌）和造血干細(xì)胞（多發(fā)性骨髓瘤和白血?。?IC50值從5 nM 到 365 nM。BMS-754807 抑制 IGF-1R-Sal細(xì)胞和RH41細(xì)胞增殖,IC50分別為7 nM 和5 nM。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | Ethanol : 85 mg/mL (184.2 mM)
H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 85 mg/mL (184.2 mM)
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| 關(guān)鍵字 | IGF-1R | BMS-754807 | Insulin Receptor | BMS 754807 | BMS754807 | inhibit | Inhibitor |
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