Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the Abl tyrosine kinase domain.
Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the Abl tyrosine kinase domain.
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DOI：
10.1371/journal.pone.0029828
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Boxer SG
中科院分区：
文献类型：
--
作者：
Levinson NM;Boxer SG
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.
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ABL酪氨酸激酶结构域中的SRC样不活跃构象。
影响因子：
9.8
作者：
Levinson NM;Kuchment O;Shen K;Young MA;Koldobskiy M;Karplus M;Cole PA;Kuriyan J
通讯作者：
Kuriyan J
影响因子：
11.4
作者：
Hubbard, SR
通讯作者：
Hubbard, SR
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
20.3
作者：
le Coutre, P;Tassi, E;Gambacorti-Passerini, C
通讯作者：
Gambacorti-Passerini, C
影响因子：
20.3
作者：
Kantarjian, Hagop M.;Giles, Francis;le Coutre, Philipp
通讯作者：
le Coutre, Philipp