Linked Life Data

21320058

Source:http://linkedlifedata.com/resource/pubmed/id/21320058

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2011-2-15
pubmed:abstractText
PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a key mediator of apoptosis induced by a wide variety of stimuli. PUMA is particularly important in initiating radiation-induced apoptosis and damage in the gastrointestinal and hematopoietic systems. Unlike most BH3-only proteins, PUMA neutralizes all five known antiapoptotic Bcl-2 members though high affinity interactions with its BH3 domain to initiate mitochondria-dependent cell death. Using structural data on the conserved interactions of PUMA with Bcl-2-like proteins, we developed a pharmacophore model that mimics these interactions. In silico screening of the ZINC 8.0 database with this pharmacophore model yielded 142 compounds that could potentially disrupt these interactions. Thirteen structurally diverse compounds with favorable in silico ADME/Toxicity profiles have been retrieved from this set. Extensive testing of these compounds using cell-based and cell-free systems identified lead compounds that confer considerable protection against PUMA-dependent and radiation-induced apoptosis, and inhibit the interaction between PUMA and Bcl-xL.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1873-4294
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
11
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
281-90
pubmed:dateRevised
2011-11-3
pubmed:meshHeading
pubmed-meshheading:21320058-Amino Acid Sequence, pubmed-meshheading:21320058-Animals, pubmed-meshheading:21320058-Apoptosis, pubmed-meshheading:21320058-Apoptosis Regulatory Proteins, pubmed-meshheading:21320058-Cell Line, Tumor, pubmed-meshheading:21320058-Cell-Free System, pubmed-meshheading:21320058-Cyclin-Dependent Kinase Inhibitor p21, pubmed-meshheading:21320058-Databases, Factual, pubmed-meshheading:21320058-Drug Design, pubmed-meshheading:21320058-Germ Cells, pubmed-meshheading:21320058-HCT116 Cells, pubmed-meshheading:21320058-Humans, pubmed-meshheading:21320058-Lymphoid Progenitor Cells, pubmed-meshheading:21320058-Mice, pubmed-meshheading:21320058-Models, Molecular, pubmed-meshheading:21320058-Molecular Dynamics Simulation, pubmed-meshheading:21320058-Molecular Sequence Data, pubmed-meshheading:21320058-Molecular Structure, pubmed-meshheading:21320058-Protein Binding, pubmed-meshheading:21320058-Protein Interaction Domains and Motifs, pubmed-meshheading:21320058-Proto-Oncogene Proteins, pubmed-meshheading:21320058-Proto-Oncogene Proteins c-bcl-2, pubmed-meshheading:21320058-Radiation-Protective Agents, pubmed-meshheading:21320058-Transfection, pubmed-meshheading:21320058-bcl-X Protein
pubmed:year
2011
pubmed:articleTitle
Development of small-molecule PUMA inhibitors for mitigating radiation-induced cell death.
pubmed:affiliation
University of Pittsburgh School of Medicine, Department of Computational & Systems Biology, HillmanCancer Center Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural