title: Inhibition of Bcr-Abl phosphorylation and induction of apoptosis by pyrazolo[3,4-d]pyrimidines in human leukemia cells.
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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pucci
authors.forename: Matteo
authors.initials: M
authors.lastname: Magnani
authors.forename: Giada A
authors.initials: GA
authors.lastname: Locatelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.forename: Antonella
authors.initials: A
authors.lastname: Naldini
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Fabio
authors.initials: F
authors.lastname: Carraro
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001665:Binding Sites; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D016313:Genes, abl / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D016392:Proto-Oncogene Proteins pp60(c-src)