Journal
NATURE
Volume 462, Issue 7276, Pages 1070-1074Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08622
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Categories
Funding
- National Institutes of Health [RO1CA11446, R01CA135257, R01CA080942, R01CA130876-02, R01CA116020, R01AG2400401, R01 CA122794, R01GM070590]
- National Cancer Institute Lung SPORE [P50CA090578]
- Cecily and Robert Harris Foundation
- Uniting Against Lung Cancer
- Flight Attendant Medical Research Institute
- Hazel and Samuel Bellin Research Fund
- Damon Runyon Foundation Cancer Innovation Award
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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(1-3). Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR(4,5). 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 wildtype 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.
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