Novel mutant-selective EGFR kinase inhibitors against EGFR T790M View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-12

AUTHORS

Wenjun Zhou, Dalia Ercan, Liang Chen, Cai-Hong Yun, Danan Li, Marzia Capelletti, Alexis B. Cortot, Lucian Chirieac, Roxana E. Iacob, Robert Padera, John R. Engen, Kwok-Kin Wong, Michael J. Eck, Nathanael S. Gray, Pasi A. Jänne

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. More... »

PAGES

1070

Journal

TITLE

Nature

ISSUE

7276

VOLUME

462

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature08622

    DOI

    http://dx.doi.org/10.1038/nature08622

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1009588480

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/20033049


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