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AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia.
Blood 2014; 123(6):905-13Blood

Abstract

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.

Authors+Show Affiliations

Oncology iMed, AstraZeneca, Waltham, MA;No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

24363397

Citation

Keeton, Erika K., et al. "AZD1208, a Potent and Selective pan-Pim Kinase Inhibitor, Demonstrates Efficacy in Preclinical Models of Acute Myeloid Leukemia." Blood, vol. 123, no. 6, 2014, pp. 905-13.
Keeton EK, McEachern K, Dillman KS, 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.
Keeton, E. K., McEachern, K., Dillman, K. S., Palakurthi, S., Cao, Y., Grondine, M. R., ... Huszar, D. (2014). AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood, 123(6), pp. 905-13. doi:10.1182/blood-2013-04-495366.
Keeton EK, et al. AZD1208, a Potent and Selective pan-Pim Kinase Inhibitor, Demonstrates Efficacy in Preclinical Models of Acute Myeloid Leukemia. Blood. 2014 Feb 6;123(6):905-13. PubMed PMID: 24363397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. AU - Keeton,Erika K, AU - McEachern,Kristen, AU - Dillman,Keith S, AU - Palakurthi,Sangeetha, AU - Cao,Yichen, AU - Grondine,Michael R, AU - Kaur,Surinder, AU - Wang,Suping, AU - Chen,Yuching, AU - Wu,Allan, AU - Shen,Minhui, AU - Gibbons,Francis D, AU - Lamb,Michelle L, AU - Zheng,Xiaolan, AU - Stone,Richard M, AU - Deangelo,Daniel J, AU - Platanias,Leonidas C, AU - Dakin,Les A, AU - Chen,Huawei, AU - Lyne,Paul D, AU - Huszar,Dennis, Y1 - 2013/12/20/ PY - 2013/12/24/entrez PY - 2013/12/24/pubmed PY - 2014/4/5/medline SP - 905 EP - 13 JF - Blood JO - Blood VL - 123 IS - 6 N2 - 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. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/24363397/AZD1208_a_potent_and_selective_pan_Pim_kinase_inhibitor_demonstrates_efficacy_in_preclinical_models_of_acute_myeloid_leukemia_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&amp;pmid=24363397 DB - PRIME DP - Unbound Medicine ER -