Abstract
Wide-ranging exploration of potential replacements for a quinoline-based inhibitor of activation of AKT kinase led to number of alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, and one such compound demonstrated pharmacodynamic knockdown of phosphorylation of AKT and downstream biomarkers in vivo and inhibition of tumor growth in a breast cancer xenograft model.
MeSH terms
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Allosteric Regulation
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Animals
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Biological Availability
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Biomarkers / metabolism
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Mice
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Mice, Nude
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Models, Molecular
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Neoplasm Transplantation
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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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Pyrazines / chemical synthesis
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Pyrazines / chemistry
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Pyrazines / pharmacology
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyridazines / chemical synthesis
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Pyridazines / chemistry
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Pyridazines / pharmacology
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology
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Quinazolines / chemical synthesis
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Quinazolines / chemistry
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Quinazolines / pharmacology
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Rats
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Biomarkers
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Heterocyclic Compounds, 3-Ring
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Heterocyclic Compounds, 4 or More Rings
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Imidazoles
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MK 2206
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Pyrazines
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Pyrazoles
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Pyridazines
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Pyridines
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Quinazolines
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Proto-Oncogene Proteins c-akt