AZD1208 is an orally bioavailable, highly selective PIM kinases inhibitor with single nanomolar potency against all three PIM kinases (IC50 of 0.4 nM, 5 nM, and 1.9 nM for Pim1, Pim2, and Pim3 in cell-free assays, respectively) and is used for treating AML.
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]
AZD-1208 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
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