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    A Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture

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    Name:
    A spiroligomer α-helix mimic ...
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    Genre
    Journal Article
    Date
    2012-10-18
    Author
    Brown, ZZ
    Akula, K
    Arzumanyan, A
    Alleva, J
    Jackson, M
    Bichenkov, E
    Sheffield, JB
    Feitelson, MA
    Schafmeister, CE
    Subject
    Binding Sites
    Biological Transport
    Cell Line, Tumor
    Diffusion
    Feedback, Physiological
    Gene Expression
    Hepatocytes
    Humans
    Imidazoles
    Kinetics
    Models, Molecular
    Molecular Conformation
    Molecular Mimicry
    Piperazines
    Protein Binding
    Protein Stability
    Protein Structure, Tertiary
    Proto-Oncogene Proteins c-mdm2
    Solid-Phase Synthesis Techniques
    Spiro Compounds
    Tumor Suppressor Protein p53
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    Permanent link to this record
    http://hdl.handle.net/20.500.12613/5446
    
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    DOI
    10.1371/journal.pone.0045948
    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 [1]. 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. © 2012 Brown et al.
    Citation to related work
    Public Library of Science (PLoS)
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    PLoS ONE
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    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.34944/dspace/5428
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