Inhibition of Bcr-Abl Phosphorylation and Induction of Apoptosis by Pyrazolo[3,4-d]pyrimidines in Human Leukemia Cells

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-pos. human leukemia cell lines (K-562, KU-812, and MEG-01), on the basis of the exptl. 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 enzymic assay on isolated c-Abl confirmed that such compds. directly inhibit Abl activity. Finally, mol. modeling simulations were also performed to hypothesize the binding mode of the compds. into the Abl binding site