Ponatinib
作者：齊岳
發布時間：2023-08-28
09:02:38
點擊數：
產品名稱：Ponatinib
產品描述：
| 產品描述 | Ponatinib is an orally available, multitargeted kinase inhibitor (IC50s: 0.37/1.1/1.5/2.2/5.4 nM for Abl, PDGFRα, VEGFR2, FGFR1, and Src, respectively). |
| 靶點活性 | PDGFRα:1.1 nM (cell free), c-Src:5.4 nM (cell free), Abl:0.37 nM (cell free), FGFR1:2.2 nM (cell free), Lyn:0.24 nM (cell free), VEGFR2:1.5 nM (cell free) |
| 體外活性 | Ponatinib (AP24534) potently inhibited native ABL (IC50: 0.37 nM), ABL T315I (IC50: 2.0 nM), and other clinically important ABL kinase domain mutants (IC50: 0.30–0.44 nM). AP24534 also inhibited SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases. AP24534 did not inhibit Aurora kinase family members, nor did it inhibit the insulin receptor or CDK2/Cyclin E. AP24534 potently inhibited proliferation of Ba/F3 cells expressing native BCR-ABL (IC50: 0.5 nM). All BCR-ABL mutants tested remained sensitive to AP24534 (IC50: 0.5–36 nM) including BCR-ABLT315I (IC50: 11 nM) [1]. Treatment with ponatinib efficiently inhibited the growth of CMPs expressing Hes1 with F/P, F/P-T674I, or F/P-D842V with an IC50 of 0.15 nM, 0.35 nM, or 1.71 nM, respectively. In accordance, ponatinib dose-dependently suppressed the activation of F/P and its downstream STAT5 and ERK in these cytokine-independent cells [2]. Ponatinib potently inhibits receptor phosphorylation and cellular proliferation with IC50 values comparable to those required for inhibition of BCR-ABL (0.3 to 20 nmol/L) [3]. |
| 體內活性 | Daily oral treatment with 2.5 or 5 mg/kg AP24534 for 19 days prolonged median survival to 27.5 and 30 days, respectively. In a xenograft model of Ba/F3 BCR-ABLT315I cells, tumor growth was inhibited by AP24534 in a dose-dependent manner compared to vehicle-treated mice, with significant suppression of tumor growth upon daily oral dosing at 10 and 30 mg/kg. Daily oral dosing of 50 mg/kg AP24534 caused significant tumor regression, with a 96% reduction in mean tumor volume at the final measurement compared to the start of treatment [1]. Ponatinib (1–25 mg/kg, p.o.) was administered orally, once daily for 28 days, to mice bearing MV4-11 xenografts. ponatinib potently inhibited tumor growth in a dose-dependent manner. Administration of 1 mg/kg led to significant inhibition of tumor growth (TGI = 46%) and doses of 2.5 mg/kg or greater resulted in tumor regression. Dosing with 10 or 25 mg/kg led to complete and durable tumor regression [3]. |
| 激酶實驗 | 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]. |
| 細胞實驗 | 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]. |
| 動物實驗 | 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]. |
| 別名 | 帕納替尼, AP24534, 普納替尼 |
| 化合物與蛋白結合的復合物 |
FGFR1 in complex with ponatinib. |
| 分子量 | 532.571 |
| 分子式 | C29H27F3N6O |
| CAS No. | 943319-70-8 |
存儲
| Powder: -20°C for 3 years | In solvent: -80°C for 2 years
溶解度
Ethanol: 26.6 mg/mL (50 mM)
DMSO: 53.3 mg/mL (100 mM)
( < 1 mg/mL refers to the product slightly soluble or insoluble )
聯系我們：
郵箱：2519696869@qq.com
QQ: 2519696869
電話：18066853083
微信：18066853083
公司介紹：
西安齊岳生物科技有限公司是集化學科研和定制與一體的高科技化學公司。業務范圍包括化學試劑和產品的研發、生產、銷售等。涉及產品為通用試劑的分銷、非通用試劑的定制與研發，涵蓋生物科技、化學品、中間體和化工材料等領域。
主營產品：COF、MOF單體系列：三蝶烯衍生物、金剛烷衍生物、四苯甲烷衍生物、peg、上轉換、石墨烯、光電材料、點擊化學、凝集素、載玻片、蛋白質交聯劑、脂質體、蛋白、多肽、氨基酸、糖化學等。
