AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia

作者：Keeton Erika K; McEachern Kristen; Dillman Keith S; Palakurthi Sangeetha; Cao Yichen; Grondine Michael R; Kaur Surinder; Wang Suping; Chen Yuching; Wu Allan; Shen Minhui; Gibbons Francis D; Lamb Michelle L; Zheng Xiaolan; Stone Richard M; DeAngelo Daniel J; Platanias Leonidas C; Dakin Les A; Chen Huawei; Lyne Paul D; Huszar Dennis^*

来源：Blood, 2014, 123(6): 905-913.

DOI：10.1182/blood-2013-04-495366

Upregulation of Pim kinases is observed in several types of leukemias and lymphomas. Pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. AZD1208 is a potent, highly selective, and orally available Pim kinase inhibitor that effectively inhibits all three isoforms at <5 nM or <150 nM in enzyme and cell assays, respectively. AZD1208 inhibited the growth of 5 of 14 acute myeloid leukemia (AML) cell lines tested, and sensitivity correlates with Pim-1 expression and STAT5 activation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells, accompanied by a dose-dependent reduction in phosphorylation of Bcl-2 antagonist of cell death, 4EBP1, p70S6K, and S6, as well as increases in cleaved caspase 3 and p27. Inhibition of p4EBP1 and p-p70S6K and suppression of translation are the most representative effects of Pim inhibition in sensitive AML cell lines. AZD1208 inhibits the growth of MOLM-16 and KG-1a xenograft tumors in vivo with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 also potently inhibits colony growth and Pim signaling substrates in primary AML cells from bone marrow that are Flt3 wild-type or Flt3 internal tandem duplication mutant. These results underscore the therapeutic potential of Pim kinase inhibition for the treatment of AML.

• 出版日期2014-2-6
• 单位西北大学