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Title: Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanism
Authors: E., Crespan
Radi, Marco
S., Zanoli
S., Schenone
Botta, Maurizio 
G., Maga
Keywords: Src; Abl; Anticancer chemotherapy; Drug resistance; Enzyme kinetics; Tyrosine kinases
Issue Date: 2010
Project: None 
The tyrosine kinase Src and its close homolog Abl, both play important roles in chronic myelogenous leukemia (CML) progression and Imatinib resistance. No clinically approved inhibitors of the drug-resistant AblT315I exist to date. Here, we present a thorough kinetic analysis of two potent dual Src-Abl inhibitors towards wild type Src and Abl, and the AblT315I mutant. Our results show that the most potent compound BO1 shows only a modest loss of potency (fourfold) towards the AblT315I mutant in vitro and was an ATP-competitive inhibitor of wild type Abl but it acted as a non-competitive inhibitor in the case of AblT315I.
ISSN: 0968-0896
DOI: 10.1016/j.bmc.2010.04.024
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