生物活性

• 靶点

  Pim3 IC50:1.9nM

  Pim2 IC50:5nM

  Pim1 IC50:0.4nM

• 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
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  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

• 动物研究
  剂量	Mice: 3 mg/kg - 30 mg/kg[1] (i.p.), 30 mg/kg - 90 mg/kg(p.o.)
  给药途径	i.p., p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01489722	Acute Myeloid Leukemia	Phase 1	Terminated	-	United States, Massachusetts ... more >> Research Site Boston, Massachusetts, United States United States, Missouri Research Site St. Louis, Missouri, United States United States, Texas Research Site Houston, Texas, United States Canada, Ontario Research Site Toronto, Ontario, Canada Collapse <<
  NCT01588548	-	-	Completed	-	-
  NCT01588548	Advanced Solid Malignancies ... more >> Malignant Lymphoma Collapse <<	Phase 1	Completed	-	Japan ... more >> Research Site Chuo-ku, Japan United Kingdom Research Site Manchester, United Kingdom Research Site Surrey, United Kingdom Collapse <<

• 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.