Premium
Inhibition of Bcr‐Abl Phosphorylation and Induction of Apoptosis by Pyrazolo[3,4‐ d ]pyrimidines in Human Leukemia Cells
Author(s) -
Manetti Fabrizio,
Pucci Annalisa,
Magnani Matteo,
Locatelli Giada A.,
Brullo Chiara,
Naldini Antonella,
Sche Silvia,
Maga Giovanni,
Carraro Fabio,
Botta Maurizio
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600214
Subject(s) - abl , proto oncogene tyrosine protein kinase src , phosphorylation , k562 cells , chemistry , tyrosine kinase , apoptosis , leukemia , philadelphia chromosome , breakpoint cluster region , cancer research , microbiology and biotechnology , tyrosine phosphorylation , biology , biochemistry , signal transduction , receptor , chromosomal translocation , immunology , gene
A series of pyrazolo[3,4‐d]pyrimidines, previously found to be Src inhibitors, was tested for their ability to inhibit proliferation of three Bcr‐Abl‐positive human leukemia cell lines (K‐562, KU‐812, and MEG‐01), on the basis of the experimental evidence that various Src inhibitors are also active against Bcr‐Abl kinase (the so called dual Src/Abl inhibitors). They reduce Bcr‐Abl tyrosine phosphorylation and promote apoptosis of the Bcr‐Abl‐expressing cells. A cell‐free enzymatic assay on isolated c‐Abl confirmed that such compounds directly inhibit Abl activity. Finally, molecular modeling simulations were also performed to hypothesize the binding mode of the compounds into the Abl binding site.