Michalczyk Anja, Klüter Sabine, Rode Haridas B, Simard Jeffrey R, Grütter Christian, Rabiller Matthias, Rauh Daniel
Chemical Genomics Centre of the Max-Planck-Society, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Bioorg Med Chem. 2008 Apr 1;16(7):3482-8. doi: 10.1016/j.bmc.2008.02.053. Epub 2008 Feb 20.
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.
最近，对激酶靶向抗癌药物的耐药性与激酶ATP结合位点的单点突变有关。在表皮生长因子受体（EGFR）中，关键的苏氨酸790（Thr790）守门残基突变为甲硫氨酸（Met），阻止了可逆性ATP竞争性抑制剂的结合。不可逆的4-（苯胺基）喹唑啉已被证明可克服这种耐药性，目前正处于临床试验阶段。为了详细了解不可逆抑制剂如何克服耐药性的结构，我们使用Src激酶作为耐药性EGFR-T790M的模型系统。我们报道了耐药激酶与不可逆抑制剂复合物的首个晶体结构。这种4-（苯胺基）喹唑啉在体外以低纳摩尔浓度抑制野生型和耐药性EGFR。耐药性cSrc-T338M激酶结构域的共晶体结构为这种活性提供了结构基础。
