Abstract
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Catalytic Domain
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Crystallography, X-Ray
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinase 2 / metabolism
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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry*
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Isoquinolines / pharmacokinetics
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Mice
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Neoplasms / drug therapy
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Phosphorylation
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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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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Rats
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Structure-Activity Relationship
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Thiadiazoles / chemical synthesis
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Thiadiazoles / chemistry*
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Thiadiazoles / pharmacokinetics
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Thiazoles / chemical synthesis
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Thiazoles / chemistry*
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Thiazoles / pharmacokinetics
Substances
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Antineoplastic Agents
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Isoquinolines
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Protein Kinase Inhibitors
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Thiadiazoles
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Thiazoles
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2-aminothiazole
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Proto-Oncogene Proteins c-akt
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Cyclic AMP-Dependent Protein Kinases
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Cyclin-Dependent Kinase 2