2qq7

Publication Abstract from PubMed

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.

Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR.,Michalczyk A, Kluter S, Rode HB, Simard JR, Grutter C, Rabiller M, Rauh D Bioorg Med Chem. 2008 Apr 1;16(7):3482-8. Epub 2008 Feb 20. PMID:18316192^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.