Linked Life Data

10441393

Source:http://linkedlifedata.com/resource/pubmed/id/10441393

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1999-9-9
pubmed:abstractText
We screened 1680 spatially separated compounds of a diverse combinatorial library of 1,4-benzodiazepines for their ability to inhibit the kinase activity of protein tyrosine kinases Src, Yes, Abl, Lck, Csk, and fibroblast growth factor receptor. This screening yielded novel ligands for the protein tyrosine kinase Src. In the 1, 4-benzodiazepine-2-one scaffold, the preferred substituent at position R(1) was 4-hydroxyphenylmethyl or a 3-indolemethyl derived from a tyrosine or tyrptophan used in building the benzodiazepine, while the substituent at R(2), introduced by alkylating agents, was preferably aromatic in nature. The preferred ring structure introduced on the bicyclic ring of the scaffold by acid chlorides was a p-hydroxy phenyl group. The lead compound, designated as N-L-Yaa, has a L-4-hydroxyphenylmethyl ring at R(1) and a biphenylmethyl substituent at R(2). The compound has an IC(50) of 73 microM against Src, 2- to 6-fold lower than against other protein tyrosine kinases and >10-fold lower than against other nucleotide-utilizing enzymes. The mechanism of binding of N-L-Yaa to Src is mixed against the peptidic substrate with a K(i) of 35 microM and noncompetitive against ATP-Mg with a K(i) of 17 microM. Multiple inhibition analysis of the lead compound in the presence of other competitive inhibitors demonstrated that the binding of the lead compound is nonexclusive to the other competitive inhibitor. The inhibitor was found to be nontoxic to the AFB-13-human fibroblasts cells and inhibited the colony formation of HT-29 colon adenocarcinoma cells that are dependent on Src activity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0003-9861
pubmed:author
pubmed:copyrightInfo
Copyright 1999 Academic Press.
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
368
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
394-400
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
1999
pubmed:articleTitle
Benzodiazepine compounds as inhibitors of the src protein tyrosine kinase: screening of a combinatorial library of 1,4-benzodiazepines.
pubmed:affiliation
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.