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.
Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms / Emmanuele Crespan;Marco Radi;Samantha Zanoli;Silvia Schenone;Maurizio Botta;Giovanni Maga. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 18(2010), pp. 3999-4008. [10.1016/j.bmc.2010.04.024]