Institute of Molecular Genetics IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
Bioorg Med Chem. 2010 Jun 1;18(11):3999-4008. doi: 10.1016/j.bmc.2010.04.024. Epub 2010 Apr 18.
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.
酪氨酸激酶Src 及其密切同源物 Abl 在慢性髓系白血病 (CML) 的进展和伊马替尼耐药中都发挥着重要作用。迄今为止，还没有临床上批准的针对耐药性 AblT315I 的药物抑制剂。在这里，我们对两种强效双重Src-Abl 抑制剂对野生型Src 和 Abl 以及 AblT315I 突变体进行了全面的动力学分析。我们的结果表明，最有效的化合物 BO1 对 AblT315I 突变体的体外活性仅有适度的降低（四倍），并且是野生型 Abl 的 ATP 竞争性抑制剂，但在 AblT315I 的情况下则表现为非竞争性抑制剂。
