Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

Article

关键词: PAN-ERBB INHIBITOR;    CELL LUNG-CANCER;    TYROSINE KINASE;    RESISTANCE;    MUTATION;    GEFITINIB;    SENSITIVITY;    NILOTINIB;    IMATINIB;    HKI-272;   

DOI  :  10.1038/nature08622

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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