| 产品描述： | AMG319 is a potent and selective PI3Kδ kinase inhibitor with IC50 of 18 nM. |
| 靶点： |
PI3Kδ:18 nM (IC50);PI3Kγ:850 nM (IC50);PI3Kβ:2.7 μM (IC50);PI3Kα:33 μM (IC50);PI3K |
| 体外研究： |
AMG319 inhibits PI3Kδ, PI3Kγ, PI3Kβ and PI3Kα with IC50s of 18 nM, 850 nM, 2.7 μM and 33 μM, respectively. AMG319, a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation. AMG319 has minimal CYP3A4/2D6 inhibition and does not inhibit CYPs (1A2, 2C8, 2C9, 2C19, 2E1, all >20 μM). There is no time dependent inhibition (TDI) against CYPs 3A4, 2D6, 1A2, and 2C9 nor CYP induction (3A4, 2D6, 1A2, 2B6) as measured in hepatocytes. AMG319 is clean in a hERG binding assay (>25 μM), and an Ames micronucleus test proved negative. AMG319 has minimal effects in a BSEP assay up to >200 μM. Additionally, AMG319 is clean in a large side effect profiling panel (CEREP) and has no activity in a large panel of 359 unique protein kinases tested at 10 μM drug concentration |
| 体内研究： |
The study is performed to determine the correlation between biochemical coverage (i.e., pAKT) with functional activity in vivo. AMG319 achieves this coverage at the 3 mg/kg level, which also coveres the human whole blood assay (HWB) (CD-69) IC90 at trough for a full 24 h period. The lower doses 0.1, 0.3, and 1 mg/kg cover trough concentrations between the HWB IC50 and IC90 and evince partial efficacy. Similarly, the plasma concentration of AMG319 covers the IC90 at the 1 mg/kg dose of the mouse anti-IgM pAKT in vitro assay |
| 细胞实验： |
Cells are seeded in 96-well plates at 2,000 (Sup-T1, Jurkat, and DND-41) or 10,000 (HPB-ALL or TALL-1) cells/well in growth media supplemented with 10% fetal bovine serum. Serial dilutions of Nirogacestat (PF-03084014) are done in DMSO, appropriate controls or designated concentrations of Nirogacestat (PF-03084014) are added to each well, and cells are incubated at 37°C for 7 days (final DMSO content 0.1%). Resazurin at a final concentration of 0.1 mg/mL is added to the cells and plates are incubated for 2 to 4 hours. Fluorescent signals are read as emission at 590 nm after excitation at 560 nm. IC50 values are calculated by using the sigmoidal dose-response (variable slope) in GraphPad Prism. |
| 动物实验： |
Mice Athymic female mice (nu/nu, 6-8 weeks) are used. For antitumor efficacy, animals bearing tumors of 150 to 300 mm3 in size are randomly divided into groups that received either vehicle (0.5% methylcellulose) or Nirogacestat (PF-03084014) (150 mg/kg, diluted in vehicle), and dosed by oral gavage. Animal body weight and tumor measurements are obtained every 2 to 3 days. Tumor volume (mm3) is measured with Vernier calipers and calculated. Percent (%) inhibition values are measured on the final day of study for drug-treated compared with vehicle-treated mice and are calculated. For all tumor growth inhibition experiments, 8 to 10 mice per dose group are used. Student's t test is used to determine the P value. |
| 参考文献： |
1. Cushing TD, et al. Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease. J Med Chem. 2015 Jan 8;58(1):480-511. |
| 溶解性： |
soluble in DMSO |
| 保存条件： |
-20℃ |
| 配置溶液浓度参考： |
|
1mg |
5mg |
10mg |
| 1 mM |
2.595 ml |
12.974 ml |
25.947 ml |
| 5 mM |
0.519 ml |
2.595 ml |
5.189 ml |
| 10 mM |
0.259 ml |
1.297 ml |
2.595 ml |
| 50 mM |
0.052 ml |
0.259 ml |
0.519 ml |
|
| 注意： |
部分产品我司仅能提供部分信息，我司不保证所提供信息的权威性，仅供客户参考交流研究之用。 |
上海工商
危险品化学品经营许可证（不带存储）
营业执照(三证合一)
北京