Abstract
Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Cell Line
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Cell Survival / drug effects
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Crystallography, X-Ray
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Drug Design*
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Drug Evaluation, Preclinical
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Humans
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Kinetics
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Mice
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Protein Structure, Tertiary
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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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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Structure-Activity Relationship
Substances
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Protein Isoforms
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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pyrazolo(1,5-a)pyrimidine
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Proto-Oncogene Proteins c-pim-1