Linked Life Data

19039816

Source:http://linkedlifedata.com/resource/pubmed/id/19039816

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2009-1-14
pubmed:abstractText
Docking simulations were used to predict the most favorable interaction between the T315I mutated form of Abl (invariably associated with resistance to the tyrosine kinase inhibitor imatinib mesylate, IM) and C6-unsubstituted and substituted pyrazolo[3,4-d]pyrimidines previously found to be dual Src/Abl inhibitors. Two C6-unsubstituted (1 and 2) and eight C6-substituted compounds (3-10) were selected and assayed for their effects on the Ba/F3 cell line transducing the wild-type p210Bcr-Abl construct, which is IM-sensitive, or three of the most common mutations associated with IM resistance in vivo (T315I, Y253F, and E255K), and driven to drug resistance by saturating doses of IL-3 or by the expression of the Bcr-Abl construct coding for the p185 protein of acute lymphoblastic leukemia. Compounds 1 and 2 were active against all cell lines assayed (LD(50) range: 0.7-4.3 microM), whereas C6-substituted compounds exhibited lower activity (LD(50) approximately 8 microM for compound 3 toward the T315I mutant). Notably, 1 and 2 were also effective toward the T315I mutation, which is insensitive to dual Src/Abl inhibitors. The cytotoxic effects of 1 and 2 on IM-sensitive and IM-resistant Ba/F3 cells were attributable, at least in part, to their pro-apoptotic activity. Taken together, such findings suggest that C6-unsubstituted pyrazolo[3,4-d]pyrimidines may represent useful inhibitors to target IM-resistant chronic myeloid leukemia.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1860-7187
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
4
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
118-26
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
C6-unsubstituted pyrazolo[3,4-d]pyrimidines are dual Src/Abl inhibitors effective against imatinib mesylate resistant chronic myeloid leukemia cell lines.
pubmed:affiliation
Istituto di Ematologia e Oncologia Medica "Lorenzo e Ariosto Seràgnoli", Università degli Studi di Bologna, Via Massarenti 9, 40138 Bologna, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't