Abstract
We demonstrate functionalized spiroligomers that mimic the HDM2-bound conformation of the p53 activation domain. Spiroligomers are stereochemically defined, functionalized, spirocyclic monomers coupled through pairs of amide bonds to create spiro-ladder oligomers. Two series of spiroligomers were synthesized, one of structural analogs and one of stereochemical analogs, from which we identified compound 1, that binds HDM2 with a Kd value of 400 nM. The spiroligomer 1 penetrates human liver cancer cells through passive diffusion and in a dose-dependent and time-dependent manner increases the levels of HDM2 more than 30-fold in Huh7 cells in which the p53/HDM2 negative feed-back loop is inoperative. This is a biological effect that is not seen with the HDM2 ligand nutlin-3a. We propose that compound 1 modulates the levels of HDM2 by stabilizing it to proteolysis, allowing it to accumulate in the absence of a p53/HDM2 feedback loop.
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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Binding Sites
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Biological Transport
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Cell Line, Tumor
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Diffusion
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Feedback, Physiological
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Gene Expression / drug effects
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Hepatocytes / drug effects*
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Hepatocytes / metabolism
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Hepatocytes / pathology
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Humans
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Imidazoles / chemistry
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Imidazoles / metabolism
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Kinetics
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Models, Molecular
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Molecular Conformation
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Molecular Mimicry
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Piperazines / chemistry
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Piperazines / metabolism
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Protein Binding
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Protein Stability / drug effects
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-mdm2 / chemistry
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Solid-Phase Synthesis Techniques
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / pharmacology*
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Tumor Suppressor Protein p53 / chemistry*
Substances
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Imidazoles
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Piperazines
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Spiro Compounds
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Tumor Suppressor Protein p53
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nutlin 3
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2