Abstract
Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (S)-14k, a potent, selective, and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary safety profiles, (S)-14k was selected for further preclinical evaluation.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Discovery
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Mice
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Models, Molecular
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Molecular Conformation
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Pyridones / administration & dosage
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Pyridones / chemistry
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Pyridones / pharmacology*
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Rats
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Small Molecule Libraries / administration & dosage
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyridones
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Small Molecule Libraries
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3