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dc.creatorBrown, ZZ
dc.creatorAkula, K
dc.creatorArzumanyan, A
dc.creatorAlleva, J
dc.creatorJackson, M
dc.creatorBichenkov, E
dc.creatorSheffield, JB
dc.creatorFeitelson, MA
dc.creatorSchafmeister, CE
dc.date.accessioned2021-01-31T21:06:36Z
dc.date.available2021-01-31T21:06:36Z
dc.date.issued2012-10-18
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/5428
dc.identifier.other23094022 (pubmed)
dc.identifier.urihttp://hdl.handle.net/20.500.12613/5446
dc.description.abstractWe 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.
dc.format.extente45948-e45948
dc.language.isoen
dc.relation.haspartPLoS ONE
dc.relation.isreferencedbyPublic Library of Science (PLoS)
dc.rightsCC BY
dc.subjectBinding Sites
dc.subjectBiological Transport
dc.subjectCell Line, Tumor
dc.subjectDiffusion
dc.subjectFeedback, Physiological
dc.subjectGene Expression
dc.subjectHepatocytes
dc.subjectHumans
dc.subjectImidazoles
dc.subjectKinetics
dc.subjectModels, Molecular
dc.subjectMolecular Conformation
dc.subjectMolecular Mimicry
dc.subjectPiperazines
dc.subjectProtein Binding
dc.subjectProtein Stability
dc.subjectProtein Structure, Tertiary
dc.subjectProto-Oncogene Proteins c-mdm2
dc.subjectSolid-Phase Synthesis Techniques
dc.subjectSpiro Compounds
dc.subjectTumor Suppressor Protein p53
dc.titleA Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture
dc.typeArticle
dc.type.genreJournal Article
dc.relation.doi10.1371/journal.pone.0045948
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.date.updated2021-01-31T21:06:32Z
refterms.dateFOA2021-01-31T21:06:37Z


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