Abstract
A series of flavone analogues were synthesized and evaluated for their antiproliferation activity against breast cancer cells. The IC(50) of compound 10 and 24 were determined to be at 5 μM. These compounds were used as baits to screen breast cancer cDNA expression phage display proteome library. DNA sequencing of the binding phages suggests that eEF1A1 is a target protein for 10 and 24. Further optimization of these compounds led to the discovery of 39 with higher cytotoxic potency (IC(50) = 1 μM) and binding to eEF1A2. Biological and biochemical data suggest that eEF1A2 might be a therapeutic target and that 39 is an excellent lead compound for further development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Bacteriophage T7 / metabolism
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Breast Neoplasms
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Female
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Flavones / chemical synthesis*
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Flavones / chemistry
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Flavones / 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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Neoplasms, Hormone-Dependent
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Peptide Elongation Factor 1 / metabolism
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Peptide Library
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Protein Binding
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Proteome / metabolism
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Receptors, Estrogen / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Surface Plasmon Resonance
Substances
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Antineoplastic Agents
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EEF1A1 protein, human
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Flavones
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Imidazoles
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Peptide Elongation Factor 1
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Peptide Library
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Proteome
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Receptors, Estrogen