| 名称 | 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. |
| 细胞实验 | 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]. |
| 激酶实验 | 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]. |
| 动物实验 | 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]. |
| 体外活性 | 方法：亲本 Ba/F3 细胞和表达天然或突变 BCR-ABL Ba/F3 细胞的用 Ponatinib (0-10000 nM) 处理 72 h，使用 MTS assay 检测细胞活力。
结果：Ponatinib 有效地抑制表达天然 BCR-ABL 的 Ba/F3 细胞的增殖 (IC50=0.5 nM)。所有测试的 BCR-ABL 突变体对 Ponatinib 保持敏感 (IC50=0.5-36 nM)，包括 BCR-ABLT315I (IC50=11 nM)。亲本 Ba/F3 细胞的生长仅在显著更高的 IC50 (1713 nM) 下受到抑制，表明对 BCR-ABL 阳性细胞的抑制具有显著的差异选择性。[1]
方法：AML 细胞系 MV4-11、Kasumi-1、KG1 和 EOL1 用 Ponatinib (0.03-100 nmol/L) 处理 1 h，使用 Western Blot 检测靶点蛋白表达水平。
结果：Ponatinib 以剂量依赖的方式抑制所有 4 种 RTK (FLT3、KIT、FGFR1 和 PDGFRα) 的磷酸化，IC50 值在 0.3-20 nmol/L 之间。[2] |
| 体内活性 | 方法：为测试体内抗肿瘤活性，将 Ponatinib (2.5-50 mg/kg in 0.5% CMC) 灌胃给药给注射 Ba/F3: BCR-ABLT315I 细胞的 SCID 小鼠，每天一次，持续十九天。
结果：Ponatinib 的治疗以剂量依赖的方式抑制肿瘤生长，延长了生存期。[1] |
| 存储条件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | Ethanol : 26.6 mg/mL (49.95 mM), Sonication is recommended.
DMSO : 16.67 mg/mL (31.3 mM), Sonication is recommended.
10% DMSO+40% PEG300+5% Tween 80+45% Saline : 5.33 mg/mL (10.01 mM), Suspension.
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| 关键字 | VEGFR2 | VEGFR | Vascular endothelial growth factor receptor | Src | Ponatinib | Platelet-derived growth factor receptor | PDGFRα | PDGFR | orally | multi-targeted | kinase | Inhibitor | inhibit | Fibroblast growth factor receptor | FGFR1 | FGFR | c-Src | c-Kit | cKit | Bcr-Abl | BcrAbl | Autophagy | AP-24534 | AP 24534 | active | Abl |
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| 相关库 | 抑制剂库 | 抗癌活性化合物库 | 经典已知活性库 | 已知活性化合物库 | EMA 上市药物库 | 抗衰老化合物库 | 膜蛋白靶向化合物库 | 药物功能重定位化合物库 | 酪氨酸激酶分子库 | FDA 上市激酶抑制剂库 | 抗癌临床化合物库 | 抗癌药物库 |