title: Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms.
abstract: 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.
authors.affiliation: Institute of Molecular Genetics IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
mesh_terms: D000255:Adenosine Triphosphate; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D050505:Mutant Proteins / Q000037:antagonists & inhibitors*; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D050505:Mutant Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases