Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR
Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR
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DOI：
10.1016/j.bmc.2008.02.053
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Rauh, Daniel
中科院分区：
文献类型：
--
作者：
Michalczyk, Anja;Klueter, Sabine;Rauh, Daniel
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Resistance to kinase- targeted cancer drugs has recently been linked to a single point mutation in the ATP binding site of the kinase. In EGFR, the crucial Thr790 gatekeeper residue is mutated to a Met and prevents reversible ATP competitive inhibitors from binding. Irreversible 4-(phenylamino) quinazolines have been shown to overcome this drug resistance and are currently in clinical trials. In order to obtain a detailed structural understanding of how irreversible inhibitors overcome drug resistance, we used Src kinase as a model system for drug resistant EGFR-T790M. We report the first crystal structure of a drug resistant kinase in complex with an irreversible inhibitor. This 4-(phenylamino) quinazoline inhibits wild type and drug resistant EGFR in vitro at low nM concentrations. The co-crystal structure of drug resistant cSrc-T338M kinase domain provides the structural basis of this activity. (C) 2008 Elsevier Ltd. All rights reserved.