Abstract
Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Cell Line
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Crystallography, X-Ray
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Humans
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Male
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Mice
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Models, Molecular
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Phosphatidylinositol 3-Kinases / chemistry
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Prostatic Neoplasms / enzymology
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Pyrazoles / chemistry
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Rats
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Solubility
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Structure-Activity Relationship
Substances
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyrazoles
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Pyridines
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Pyrimidines
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pyridine