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A Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture
Brown, ZZ Akula, K Arzumanyan, A Alleva, J Jackson, M Bichenkov, E Sheffield, JB Feitelson, MA Schafmeister, CE
Brown, ZZ
Akula, K
Arzumanyan, A
Alleva, J
Jackson, M
Bichenkov, E
Sheffield, JB
Feitelson, MA
Schafmeister, CE
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Genre
Journal Article
Date
2012-10-18
Advisor
Committee member
Group
Department
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
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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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.
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PLoS ONE
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