Abstract
From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Anilides / chemistry
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Anilides / pharmacokinetics
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Anilides / pharmacology
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Class Ia Phosphatidylinositol 3-Kinase / metabolism
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Crystallography, X-Ray
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Female
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Gene Deletion
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Humans
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Male
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Mice
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Mice, SCID
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Models, Molecular
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PTEN Phosphohydrolase / genetics
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Phosphoinositide-3 Kinase Inhibitors*
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Prostate / cytology
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Prostate / drug effects
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / genetics
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Pyrimidinones / chemistry*
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Pyrimidinones / pharmacokinetics
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Pyrimidinones / pharmacology*
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Structure-Activity Relationship
Substances
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Anilides
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Antineoplastic Agents
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Phosphoinositide-3 Kinase Inhibitors
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Protein Isoforms
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Pyrimidinones
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Class Ia Phosphatidylinositol 3-Kinase
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PTEN Phosphohydrolase
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PTEN protein, human