Inhibition of Bcr-Abl phosphorylation and induction of apoptosis by pyrazolo[3,4-d]pyrimidines in human leukemia cells |
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Authors: | Manetti Fabrizio Pucci Annalisa Magnani Matteo Locatelli Giada A Brullo Chiara Naldini Antonella Schenone Silvia Maga Giovanni Carraro Fabio Botta Maurizio |
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Affiliation: | Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy. |
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Abstract: | 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. |
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Keywords: | drug design dual Src/Abl inhibitors leukemia cell inhibitors medicinal chemistry pyrazolo[3,4‐d]pyrimidines |
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