Abstract
Serine/threonine kinase PIM3 is a potential therapeutic target for pancreatic cancer. Here, we describe the evolution of our previous PIM1 inhibitor 1 into PIM3 inhibitor 11 guided by use of the crystal structure of PIM1 as a surrogate to provide a basis for rational modification. Compound 11 potently inhibits PIM3 kinase activity, as well as growth of several pancreatic cancer cell lines. In a mouse xenograft model, 11 inhibited growth of human pancreatic cancer cell line PCI66 with negligible body weight loss. Thus, 11 appears to be a promising lead compound for further optimization to develop new anti-pancreatic cancer agents.
Keywords:
Anti-cancer agent; Drug design; Kinase inhibitor; PIM3; Pancreatic cancer.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Binding Sites
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Cell Line, Tumor
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Drug Design*
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Humans
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Inhibitory Concentration 50
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Mice
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Mice, Nude
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Molecular Dynamics Simulation
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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PIM3 protein, human
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Protein Serine-Threonine Kinases