Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms

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• 作者：Emmanuele Crespan ; Marco Radi ; Samantha Zanoli ; Silvia Schenone ; Maurizio Botta ; Giovanni Maga
• 关键词：Src ; Abl ; Anticancer chemotherapy ; Drug resistance ; Enzyme kinetics ; Tyrosine kinases
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2010
• 出版时间：1 June 2010
• 年：2010
• 卷：18
• 期：11
• 页码：3999-4008
• 全文大小：950 K

文摘

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.