| 名稱 | Ponatinib |
| 描述 | Ponatinib (AP24534) is a multi-targeted kinase inhibitor with oral activity that inhibits Abl, PDGFRα, VEGFR2, FGFR1, and Src (IC50=0.37/1.1/1.5/2.2/5.4 nM). Ponatinib has antitumor activity for the treatment of chronic granulocytic leukemia in adults. leukemia. |
| 細(xì)胞實(shí)驗(yàn) | Ba/F3 cell lines were distributed in 96-well plates (4 × 10^3 cells/well) and incubated with escalating concentrations of AP24534 for 72 hr. The inhibitor ranges used were: 0–625 nM for cells expressing BCR-ABL and 0–10,000 nM for BCR-ABL negative cells. Proliferation was measured using an MTS-based viability assay. IC50 values are reported as the mean of three independent experiments performed in quadruplicate. For cell proliferation experiments with CML or normal primary cells, mononuclear cells were plated in 96-well plates (5 × 10^4 cells/well) over graded concentrations of AP24534 (0–1000 nM) in RPMI supplemented with 10% FBS, L-glutamine, penicillin/streptomycin, and 100 μM β-mercaptoethanol. Following a 72 hr incubation, cell viability was assessed by subjecting cells to an MTS assay. All values were normalized to the control wells with no drug [1]. |
| 激酶實(shí)驗(yàn) | AP24534 was profiled against >100 kinases by Reaction Biology Corporation using the Kinase Hotspot assay, which utilizes 10 μM [33P]-ATP, recombinant kinase domain, peptide substrate, and a range of 10 concentrations of inhibitor to establish an IC50 value [1]. |
| 動(dòng)物實(shí)驗(yàn) | Briefly, tumor xenografts were established by the subcutaneous implantation of MV4-11 cells (1 × 10^7 in 50% Matrigel) into the right flank of female CB.17 severe combined immunodeficient mice and dosing was initiated when the average tumor volume reached approximately 200 mm^3. Ponatinib was formulated in aqueous 25 mmol/L citrate buffer (pH = 2.75) and mice were dosed orally once daily for 4 weeks. The tumors were measured in 2 dimensions (length and width) with a caliper in millimeters. Tumor volume (mm3) was calculated with the following formula: tumor volume = (length × width^2)/2. Tumor growth inhibition (TGI) was calculated as follows: TGI = (1 ? ΔT/ΔC) × 100, where ΔT stands for mean tumor volume change of each treatment group and ΔC for mean tumor volume change of control group. The tumor volume data were collected and analyzed with a 1-way ANOVA test to determine the overall difference among groups. Each ponatinib treatment group was further compared to the vehicle control group for statistical significance using Dunnett's Multiple Comparison Test. A P-value less than 0.05 was considered to be statistically significant and a P-value less than 0.01 to be highly statistically significant [3]. |
| 體外活性 | 方法：親本 Ba/F3 細(xì)胞和表達(dá)天然或突變 BCR-ABL Ba/F3 細(xì)胞的用 Ponatinib (0-10000 nM) 處理 72 h，使用 MTS assay 檢測(cè)細(xì)胞活力。
結(jié)果：Ponatinib 有效地抑制表達(dá)天然 BCR-ABL 的 Ba/F3 細(xì)胞的增殖 (IC50=0.5 nM)。所有測(cè)試的 BCR-ABL 突變體對(duì) Ponatinib 保持敏感 (IC50=0.5-36 nM)，包括 BCR-ABLT315I (IC50=11 nM)。親本 Ba/F3 細(xì)胞的生長(zhǎng)僅在顯著更高的 IC50 (1713 nM) 下受到抑制，表明對(duì) BCR-ABL 陽性細(xì)胞的抑制具有顯著的差異選擇性。[1]
方法：AML 細(xì)胞系 MV4-11、Kasumi-1、KG1 和 EOL1 用 Ponatinib (0.03-100 nmol/L) 處理 1 h，使用 Western Blot 檢測(cè)靶點(diǎn)蛋白表達(dá)水平。
結(jié)果：Ponatinib 以劑量依賴的方式抑制所有 4 種 RTK (FLT3、KIT、FGFR1 和 PDGFRα) 的磷酸化，IC50 值在 0.3-20 nmol/L 之間。[2] |
| 體內(nèi)活性 | 方法：為測(cè)試體內(nèi)抗腫瘤活性，將 Ponatinib (2.5-50 mg/kg in 0.5% CMC) 灌胃給藥給注射 Ba/F3: BCR-ABLT315I 細(xì)胞的 SCID 小鼠，每天一次，持續(xù)十九天。
結(jié)果：Ponatinib 的治療以劑量依賴的方式抑制腫瘤生長(zhǎng)，延長(zhǎng)了生存期。[1] |
| 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 : 26.6 mg/mL (50 mM)
DMSO : 16.67 mg/mL (31.3 mM)
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 5.33 mg/mL (10.01 mM), Please add co-solvents sequentially, clarifying the solution as much as possible before adding the next one. Dissolve by heating and/or sonication if necessary. Working solution is recommended to be prepared and used immediately.
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| 關(guān)鍵字 | Src | Ponatinib | Platelet-derived growth factor receptor | Bcr-Abl | orally | inhibit | multi-targeted | VEGFR2 | Fibroblast growth factor receptor | Abl | VEGFR | active | PDGFR | AP 24534 | FGFR | Inhibitor | AP-24534 | PDGFRα | kinase | FGFR1 | Autophagy | Vascular endothelial growth factor receptor |
| 相關(guān)產(chǎn)品 | Guanidine hydrochloride | Naringin | Valproic Acid | Taurine | Gefitinib | Aceglutamide | Hydroxychloroquine | Ferulic Acid | Curcumin | Stavudine | Paeonol | Sodium 4-phenylbutyrate |
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