Department of Chemistry, Stanford University, Stanford, California, United States of America.
PLoS One. 2012;7(4):e29828. doi: 10.1371/journal.pone.0029828. Epub 2012 Apr 6.
Chronic myeloid leukemia (CML) is caused by the kinase activity of the BCR-Abl fusion protein. The Abl inhibitors imatinib, nilotinib and dasatinib are currently used to treat CML, but resistance to these inhibitors is a significant clinical problem. The kinase inhibitor bosutinib has shown efficacy in clinical trials for imatinib-resistant CML, but its binding mode is unknown. We present the 2.4 Å structure of bosutinib bound to the kinase domain of Abl, which explains the inhibitor's activity against several imatinib-resistant mutants, and reveals that similar inhibitors that lack a nitrile moiety could be effective against the common T315I mutant. We also report that two distinct chemical compounds are currently being sold under the name "bosutinib", and report spectroscopic and structural characterizations of both. We show that the fluorescence properties of these compounds allow inhibitor binding to be measured quantitatively, and that the infrared absorption of the nitrile group reveals a different electrostatic environment in the conserved ATP-binding sites of Abl and Src kinases. Exploiting such differences could lead to inhibitors with improved selectivity.
慢性髓性白血病（CML）是由 BCR-Abl 融合蛋白的激酶活性引起的。目前，Abl 抑制剂伊马替尼、尼罗替尼和达沙替尼被用于治疗 CML，但对这些抑制剂的耐药性是一个重大的临床问题。激酶抑制剂博舒替尼在治疗伊马替尼耐药性 CML 的临床试验中显示出疗效，但它的结合模式尚不清楚。我们呈现了博舒替尼与 Abl 激酶结构域结合的 2.4Å 结构，该结构解释了抑制剂对几种伊马替尼耐药突变体的活性，并且表明缺乏腈基部分的类似抑制剂可能对常见的 T315I 突变体有效。我们还报告说，目前有两种不同的化学化合物以“博舒替尼”的名义出售，并报告了它们的光谱和结构特征。我们表明，这些化合物的荧光特性允许定量测量抑制剂的结合，并且腈基的红外吸收揭示了 Abl 和 Src 激酶的保守 ATP 结合位点中的不同静电环境。利用这些差异可以开发出具有更高选择性的抑制剂。
