AT7519 Hydrochloride
货号：
IA3790
品牌：
Jinpan
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产品简介
| MDL | MFCD14636428 |
| 别名 | N-(4-哌啶基)-4-(2,6-二氯苄氨基)-1H-吡唑-3-羧胺盐酸盐 |
| CAS | 902135-91-5 |
| 分子式 | C16H18Cl3N5O2 |
| 分子量 | 418.71 |
| 储存条件 | 2-8℃ |
| 纯度 | ≥98% |
| 单位 | 瓶 |
| 生物活性 | AT7519是一种ATP竞争性CDK抑制剂，对CDK1的Ki值为38 nM。[1] |
| In Vitro | AT7519对所有非CDK激酶没有活性，除了GSK3β (IC50 = 89 nM)。AT7519在各种人肿瘤细胞系中表现出有效的抗增殖活性，IC50值范围为40 nM(对MCF-7)到940 nM(对SW620)，与对CDK1和CDK2的抑制一致。[1] AT7519在多发性骨髓瘤(MM)细胞系中诱导剂量依赖性细胞毒性，在48小时，IC50值范围为0.5到2 μM，最敏感的细胞系为MM.1S (0.5 μM)和U266 (0.5 μM)，最耐药的是MM.1R (>2 μM)。它在外周血单核细胞(PBMNC)中不会诱导细胞毒性。AT7519部分抑制IL6和IGF-1诱导的增殖优势，以及骨髓基质细胞(BMSCs)的保护作用。AT7519在丝氨酸2和丝氨酸5位点诱导快速的RNA pol II CTD去磷酸化，并导致转录的抑制，部分有助于AT7519诱导的MM细胞的细胞毒性。AT7519通过下调GSK-3β磷酸化诱导GSK-3β的活化，这也有助于AT7519诱导的独立于转录抑制的细胞凋亡。[2] |
| In Vivo | 在HCT116和HT29结肠癌异种移植物模型中，AT7519 (9.1 mg/kg)每天两次给药引起早期和晚期皮下注射的肿瘤退化。[1]在人MM异种移植小鼠模型中，AT7519治疗(15 mg/kg)抑制肿瘤生长，并延长小鼠平均整体存活期，这与增加的caspase 3活化相关。[2] |
| SMILES | O=C(C(C(Cl)=CC=C1)=C1Cl)NC2=CNN=C2C(NC3CCNCC3)=O.[H]Cl |
| 靶点 | CDK9/CyclinT，CDK5/p35，CDK2/CyclinA，，CDK4/CyclinD1;GSK-3β |
| 动物实验 | For cell cycle analysis in an asynchronous population,0.5x106cells/mL medium were seeded onto 6-well tissue culture plates and allowed to recover for 16 h. AT7519 or vehicle control (0.1% DMSO) was added for 24 h. Cells were harvested and fixed in 2 mL of 70% ethanol. Cells were collected by centrifugation and washed with 1 mL PBS. Samples were centrifuged again and resuspended in 1 mL PBS containing 50 Ag/mL propidium iodide and 0.1 mg/mL RNase. Cells were incubated at 37℃ for 30 min and then analyzed by flow cytometry to determine propidium iodide incorporation using a BD FACSCalibur and CellQuest Pro analysis software. In the case of block and release experiments, cells were seeded at a concentration of 0.5x106per plate onto 10 cm dishes (MRC-5) or 3×105 per well onto a 6-well plate (HCT116) and allowed to recover overnight. Cells were transferred to serum-free medium for 24 h or treated with 2 mmol/L thymidine for 16 h as indicated. Following cell cycle arrest, cells were returned to complete, fresh medium containing AT7519 for various times as indicated in the figures below. Following incubation, cells were harvested and analyzed as above.[1] |
| 细胞实验 | Experiments on mice bearing HCT116 xenografts were done by Molecular Imaging Research. Female ICR severe combined immunodeficient mice were purchased from Taconic Farms and housed in pathogen-free conditions according to procedures approved by MIR Animal Care and Use Committee. Four-week-old animals were implanted s.c. on day 0 with 30 to 60 mg tumor fragments using a 12-gauge Trocar. Treatment started on day 12 after implantation for the early-stage HCT116 xenograft study (tumor volume range,75-150 mm3; 8 mice per group) and on day 15 for the study using advanced-stage tumors (275-550 mm3; 12 mice per group). Mice were dosed according to schedule. Tumor dimensions were measured every 2 or 3 days and the volume was calculated according to the equation: length x width2 x 0.5. Experiments using male BALB/c nu/nu mice were done according to UK Animals (Scientific Procedures) Act 1986. Animals were purchased from Harlan UK and housed in pathogen-free conditions. Six- to 8-week-old male BALB/c Hsd:athymic nude-Foxn1nu mice were implanted s.c. with one HT29 tumor fragment per mouse into the right flank. Five days after implantation,mice were arranged into groups of 12 according to tumor volume with a mean volume of 75 mm3 (range,50-130 mm3). Mice were then dosed according to schedule. Tumor volume was measured every 2 to 3 days as above.[1] |
| 数据来源文献 | [1] Squires MS, et al. Mol Cancer Ther, 2009, 8(2), 324-332. [2] Santo L, et al. Oncogene, 2010, 29(16), 2325-2336. |
| 规格 | 5mg 10mg |
AT7519 HCl是一种多重CDK抑制剂。