Abstract
The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Binding Sites
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Cell Line
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Crystallography, X-Ray
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Drug Design
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Drug Evaluation, Preclinical
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High-Throughput Screening Assays
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Humans
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Mice
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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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-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Pyrroles / chemical synthesis
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Pyrroles / chemistry*
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Pyrroles / pharmacology
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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AKT1S1 protein, human
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Adaptor Proteins, Signal Transducing
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Phosphoproteins
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Protein Isoforms
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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pyrrolopyrimidine
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Proto-Oncogene Proteins c-akt