title: Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.
abstract: The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Cai-Hong
authors.initials: CH
authors.lastname: Yun
authors.forename: Danan
authors.initials: D
authors.lastname: Li
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.forename: Alexis B
authors.initials: AB
authors.lastname: Cortot
authors.forename: Lucian
authors.initials: L
authors.lastname: Chirieac
authors.forename: Roxana E
authors.initials: RE
authors.lastname: Iacob
authors.forename: Robert
authors.initials: R
authors.lastname: Padera
authors.forename: John R
authors.initials: JR
authors.lastname: Engen
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D008168:Lung / Q000187:drug effects; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors