Document Detail


Development of Small-Molecule PUMA Inhibitors for Mitigating Radiation-Induced Cell Death.
MedLine Citation:
PMID:  21050170     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Gabriela Mustata; Mei Li; Nicki Zevola; Ahmet Bakan; Lin Zhang; Michael Epperly; Joel S Greenberger; Jian Yu; Ivet Bahar
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2010-11-4
Journal Detail:
Title:  Current topics in medicinal chemistry     Volume:  -     ISSN:  1873-4294     ISO Abbreviation:  -     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101119673     Medline TA:  Curr Top Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Computational & Systems, University of Pittsburgh School of Medicine, Biology, 5117 Centre Ave, Pittsburgh, PA, 15213, USA. bahar@pitt.edu.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Modulation of Protein-Protein Interactions as a Therapeutic Strategy for the Treatment of Neurodegen...
Next Document:  GABA(A) Receptor Subtype-Selective Modulators. II. ?5-Selective Inverse Agonists for Cognition Enhan...