Brivanib (alaninate)
作者：齊岳
發(fā)布時(shí)間：2023-08-28
09:00:55
點(diǎn)擊數(shù)：
產(chǎn)品名稱：Brivanib (alaninate)
產(chǎn)品描述：
| 產(chǎn)品描述 | Brivanib Alaninate is the alaninate salt of a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor with potential antineoplastic activity. Brivanib strongly binds to and inhibits VEGFR2, a tyrosine kinase receptor expressed almost exclusively on vascular endothelial cells; inhibition of VEGFR2 may result in inhibition of tumor angiogenesis, inhibition of tumor cell growth, and tumor regression. |
| 靶點(diǎn)活性 | Flk1:89 nM, FGFR1:148 nM, VEGFR1:380 nM, VEGFR2:25 nM |
| 體外活性 | 25 mg/kg BMS-582664在大鼠中AUC為13.4 μM×hr,Cmax為6.4 μM.50 mg/kg BMS-582664在小鼠中AUC為136 μM×hr,Cmax為41 μM.50 mg/kg和100 mg/kg BMS-582664作用于攜帶病患衍生的移植瘤06-0606 的小鼠,抑制腫瘤生長(zhǎng)速度分別為55% 和13%.口服60 mg/kg BMS-582664顯著降低攜帶病患衍生的移植瘤06-0606 的小鼠中腫瘤重量,促進(jìn)細(xì)胞凋亡,降低微血管密度,抑制細(xì)胞增殖,并下調(diào)細(xì)胞周期調(diào)控.小鼠口服60 mg/kg BMS-582664,迅速吸收,Tmax為1小時(shí),半衰期 (t1/2)為2.7小時(shí),平均滯留時(shí)間為3.6小時(shí).60 mg/kg和90 mg/kg BMS-582664劑量依賴性抑制攜帶H3396移植瘤的無(wú)胸腺小鼠中腫瘤生長(zhǎng),腫瘤生長(zhǎng)抑制率分別為85%和97%.80 mg/kg和107 mg/kg.BMS-582664 處理攜帶L2987非小細(xì)胞肺癌移植瘤的無(wú)胸腺小鼠,劑量依賴性抑制腫瘤生長(zhǎng),腫瘤生長(zhǎng)抑制率分別為85% 和 97%.100 mg/kg BMS-582664抑制兩種攜帶移植瘤的小鼠模型（L2987和HCT116）中血管內(nèi)皮細(xì)胞的增長(zhǎng). |
| 體內(nèi)活性 | BMS-582664固態(tài)穩(wěn)定性較高,在50°C下放置干燥劑的12周期間僅有0.3％降解,在pH為6.5時(shí)也具有較好的液態(tài)穩(wěn)定性。2 μM BMS-582664明顯抑制VEGF和 bFGF刺激的SK-HEP1細(xì)胞和HepG-2細(xì)胞中VEGFR-2,FGFR-1,ERK1/2和Akt的磷酸化,而B(niǎo)MS-582664單獨(dú)作用于未經(jīng)刺激的細(xì)胞,則不影響ERK1/2,Akt,VEGFR-2和FGFR-1的磷酸化水平。BMS-582664抑制VEGF和FGF刺激的HUVECs 增殖,IC50分別為40 nM和276 nM。BMS-582664抑制CYP2C19,CYP3A4(BFC)和CYP3A4 (BzRes)細(xì)胞,IC50分別為2.4 μM,0.51 μM和1.6 μM。 |
| 激酶實(shí)驗(yàn) | Kinase inhibition assays: For the VEGFR2, Flk1 and FGFR1 kinase assays, BMS-582664 is dissolved in DMSO and diluted with water/10% DMSO to a final DMSO concentration of 2%. The kinase reactions consists of 8 ng of enzymes with GST tag, 75 μg/mL substrate, 1 μM ATP, and 0.04 μCi [γ-33P]ATP in 50 μL total reaction volume (kinase buffer:? 20 mM Tris, pH 7.0, 25 μg/mL BSA, 1.5 mM MnCl2, 0.5 mM dithiothreitol). In all cases, the reactions are incubated for 60 min at 27℃ and terminated with the addition of cold trichloroacetic acid (TCA) to a final concentration of 15%. The percent inhibition from the kinase assays is determined by nonlinear regression analyses, and data are reported as the inhibitory concentration required to achieve 50% inhibition relative to control reactions (IC50). |
| 細(xì)胞實(shí)驗(yàn) | Cells are grown in 100 μL of minimal growth medium and 1.0% heat-inactivated fetal bovine serum in 96-well collagen IV coated plates at a density of 2 × 103 per well in a 37 ℃/5% CO2 environment. Twenty-four hours later, serum is adjusted to 10%, and BMS-582664 at various dilutions are added to each well in a final volume of minimal growth media that contains 10% serum. Forty-eight hours later, 0.5 μCi of [3H]thymidine is added in a volume of 20 μL of minimal media for 24 hours. Plates are washed once in PBS. Upon removal of PBS, Trypsin is added to cells which are subsequently harvested onto glass-fiber filters using an automated harvestor. Incorporated tritium is quantified using a β-counter. Dose?response curves are generated to determine the IC50 value, which is defined as the concentration of drug required to inhibit 50% of tritium incorporation when compared to untreated serum-stimulated cells.(Only for Reference) |
| 別名 | 丙氨酸布立尼布, BMS-582664, Brivanib Alaninate |
| 分子量 | 441.46 |
| 分子式 | C22H24FN5O4 |
| CAS No. | 649735-63-7 |
存儲(chǔ)
Powder: -20°C for 3 years | In solvent: -80°C for 2 years
溶解度
Ethanol: 82 mg/mL (185.7 mM)
DMSO: 82 mg/mL (185.7 mM)
( < 1 mg/mL refers to the product slightly soluble or insoluble )
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