Linked Life Data

20405848

Source:http://linkedlifedata.com/resource/pubmed/id/20405848

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2010-5-6
pubmed:abstractText
Development of inhibitors to antagonize the activities of antiapoptotic Bcl-2 family proteins is of particular interest in cancer chemotherapy. We discovered a quinazoline-2(1H)-thione derivative (DCBL55) as a new Bcl-x(L), Bcl-2, and Mcl-1 inhibitor by virtual database screening. We systematically modified the structure of compound 1 by chemical synthesis. The interactions of the compounds with Bcl-x(L) were predicted by molecular modeling simulations, which were confirmed by structure-activity relationship analysis and protein mutation studies. Three locations at the hydrophobic groove of Bcl-x(L), referred to as P2, P4, and P5, were found to contribute to the ligand interactions. Although the compounds induced mitochondrial potential reduction, caspase activation, and ROS generation, the cytotoxicities and the ultrastructural changes of outer mitochondrial membrane suggested that the compounds may target additional proteins outside the Bcl-2 family. Altogether, the present study provides new lead compounds and critical structural information for further development of more potent and specific inhibitors of antiapoptotic Bcl-2 family proteins.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1520-4804
pubmed:author
pubmed:issnType
Electronic
pubmed:day
13
pubmed:volume
53
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3465-79
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Design, synthesis, and interaction study of quinazoline-2(1H)-thione derivatives as novel potential Bcl-xL inhibitors.
pubmed:affiliation
Department of Molecular Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't