Abstract
A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4'-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC(50) values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined.
MeSH terms
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Adenosine Triphosphate / metabolism
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Antineoplastic Agents* / chemical synthesis
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Antineoplastic Agents* / pharmacology
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Binding Sites
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Cell Proliferation / drug effects
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Enzyme Inhibitors* / chemical synthesis
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Enzyme Inhibitors* / pharmacology
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Ethylenes* / chemical synthesis
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Ethylenes* / pharmacology
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Glycogen Synthase Kinase 3
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Humans
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Neoplasms / drug therapy*
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Ethylenes
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Adenosine Triphosphate
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3