title: Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR.
abstract: 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.
authors.affiliation: Chemical Genomics Centre of the Max-Planck-Society, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Michalczyk
authors.forename: Sabine
authors.initials: S
authors.lastname: Klüter
authors.forename: Haridas B
authors.initials: HB
authors.lastname: Rode
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Simard
authors.forename: Christian
authors.initials: C
authors.lastname: Grütter
authors.forename: Matthias
authors.initials: M
authors.lastname: Rabiller
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
mesh_terms: D018360:Crystallography, X-Ray; D004351:Drug Resistance / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors