A Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture
dc.creator | Brown, ZZ | |
dc.creator | Akula, K | |
dc.creator | Arzumanyan, A | |
dc.creator | Alleva, J | |
dc.creator | Jackson, M | |
dc.creator | Bichenkov, E | |
dc.creator | Sheffield, JB | |
dc.creator | Feitelson, MA | |
dc.creator | Schafmeister, CE | |
dc.date.accessioned | 2021-01-31T21:06:36Z | |
dc.date.available | 2021-01-31T21:06:36Z | |
dc.date.issued | 2012-10-18 | |
dc.identifier.issn | 1932-6203 | |
dc.identifier.issn | 1932-6203 | |
dc.identifier.doi | http://dx.doi.org/10.34944/dspace/5428 | |
dc.identifier.other | 23094022 (pubmed) | |
dc.identifier.uri | http://hdl.handle.net/20.500.12613/5446 | |
dc.description.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. | |
dc.format.extent | e45948-e45948 | |
dc.language.iso | en | |
dc.relation.haspart | PLoS ONE | |
dc.relation.isreferencedby | Public Library of Science (PLoS) | |
dc.rights | CC BY | |
dc.subject | Binding Sites | |
dc.subject | Biological Transport | |
dc.subject | Cell Line, Tumor | |
dc.subject | Diffusion | |
dc.subject | Feedback, Physiological | |
dc.subject | Gene Expression | |
dc.subject | Hepatocytes | |
dc.subject | Humans | |
dc.subject | Imidazoles | |
dc.subject | Kinetics | |
dc.subject | Models, Molecular | |
dc.subject | Molecular Conformation | |
dc.subject | Molecular Mimicry | |
dc.subject | Piperazines | |
dc.subject | Protein Binding | |
dc.subject | Protein Stability | |
dc.subject | Protein Structure, Tertiary | |
dc.subject | Proto-Oncogene Proteins c-mdm2 | |
dc.subject | Solid-Phase Synthesis Techniques | |
dc.subject | Spiro Compounds | |
dc.subject | Tumor Suppressor Protein p53 | |
dc.title | A Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture | |
dc.type | Article | |
dc.type.genre | Journal Article | |
dc.relation.doi | 10.1371/journal.pone.0045948 | |
dc.ada.note | For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu | |
dc.date.updated | 2021-01-31T21:06:32Z | |
refterms.dateFOA | 2021-01-31T21:06:37Z |