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AZD-1208

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Chemical Structure| 1204144-28-4 同义名 : -
CAS号 : 1204144-28-4
货号 : A178546
分子式 : C21H21N3O2S
纯度 : 98%
分子量 : 379.475
MDL号 : MFCD25976757
存储条件：

粉末 Keep in dark place,Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(131.76 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+30% PEG300+water 2 mg/mL clear

PO 0.5% CMC-Na 43 mg/mL suspension

生物活性
靶点

  • Pim3

    Pim3, IC50:1.9 nM

  • Pim1

    Pim1, IC50:0.4 nM

  • Pim2

    Pim2, IC50:5 nM
描述 Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of pim kinase, identified as proviral insertion sites of the Moloney murine leukemia virus associated with the development of T-cell lymphomas. Pim kinase can modulate the activity of a variety of substrates involved in the control of transcription, translation, cell proliferation and survival, such as promoting survival of AML cells via phosphorylation of Bcl-2 antagonist of cell death (BAD), sharing other substrates with the AKT pathway. Pim-1 has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies. AZD1208 is a potent and highly selective Pim inhibitor with Ki values of 0.1 nM, 1.92 nM and 0.4 nM for Pim-1, Pim-2 and Pim-3 (measured by purified human Pim enzyme assays), respectively. AZD1208 could inhibit growth of partial AML cell-line expressing high Pim-1 and phosphorylated STAT5 with GI50<1 μM, like EOL-1, KG-1a, Kasumi-3, MV4-11 and MOLM-16 with GI50 values of 0.06, 0.6, 0.3, 0.9 and 0.02 μM, respectively. It also induced cell-cycle arrest and apoptosis in sensitive MOLM-16 cells. After treatment with 1 μM AZD1208 for 72h, G0/G1 and subG1 populations were increased. The increase in the percentage of apoptotic and dead cells can also be observed in MOLM-16 cells. Varying degrees of inhibition of p-BAD, as well as inhibition of phosphorylation of the mTORC1 inhibitory protein PRAS40 on Thr246 were seen in both resistant cells and sensitive cells after treatment with 1 μM AZD1208, but significant reduced interaction of immunoprecipitated eIF4E with eIF4G and increased interaction with inhibitory 4EBP1 that correlated with reduced p-4EBP1 can be only observed in sensitive cells MOLM-16, EOL-1 and KG-1a. A marked suppression of polysomal peaks with a reciprocal increase in the 80S monosome peak can also be seen in sensitive EOL-1 cells after 1 μM AZD1208 for 9 hours. These indicated that it was inhibition of p4EBP1 and p-p70S6K and suppression of translation, but not pBAD, necessarily correlate with growth inhibition or apoptosis in these cell lines. Oral dose of 30 mg/kg AZD1208 inhibited the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic to pharmacokinetic relationship[1].
作用机制 AZD1208 is a potent ATP-competitive inhibitor of all three Pim kinase isoforms.[1]
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
MOLM16 cells Proliferation assay 72 h Antiproliferative activity against human MOLM16 cells after 72 hrs by Cell Titer-Blue assay, GI50=0.02 μM 22727640
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.64mL

0.53mL

0.26mL

13.18mL

2.64mL

1.32mL

26.35mL

5.27mL

2.64mL
参考文献

[1]Keeton EK, McEachern K, et al. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood. 2014;123(6):905-13.

[2]Mo G, Gibbons F, et al. Lifespan based pharmacokinetic-pharmacodynamic model of tumor growth inhibition by anticancer therapeutics. PLoS One. 2014;9(10):e109747.