Abstract
A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50) <30 nM). This work delivers an excellent lead-optimization platform for Pim targeting anticancer therapies.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Humans
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Leukemia / drug therapy
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Naphthyridines / chemistry*
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Naphthyridines / pharmacology*
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Neoplasms / drug therapy
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-pim-1 / metabolism
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Triazoles / chemistry
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Triazoles / pharmacology
Substances
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Antineoplastic Agents
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Naphthyridines
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PIM2 protein, human
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Triazoles
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1,2,4-triazole
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-pim-1