title: Discovery of selective irreversible inhibitors for EGFR-T790M.
abstract: Targeting the epidermal growth factor receptor kinase (EGFR) with ATP-competitive kinase inhibitors results in dramatic but short-lived responses in patients with EGFR mutant non small cell lung cancer. A series of novel covalent EGFR kinase inhibitors with selectivity for the clinically relevant T790M 'gatekeeper' resistance mutation relative to wild-type EGFR were discovered by library screening. A representative compound 3i was obtained through a systematic SAR study guided by mutant EGFR-dependent cellular proliferation assays.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D066246:ErbB Receptors