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Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

机译：新型针对EGFR T790M的突变体选择性EGFR激酶抑制剂

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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. 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.
机译：表皮生长因子受体（EGFR）激酶抑制剂在EGFR突变型非小细胞肺癌（NSCLC）中的临床疗效受到耐药性突变（包括Gatekeeper T790M突变）的发展的限制。用不可逆抑制剂靶向EGFR T790M的策略取得了有限的成功，并且由于同时抑制野生型EGFR而与毒性相关。当前所有的EGFR抑制剂均具有与结构相关的基于喹唑啉的核心骨架，并被确定为野生型EGFR的ATP竞争性抑制剂。在这里，我们通过筛选针对EGFR T790M的不可逆激酶抑制剂库来鉴定共价嘧啶EGFR抑制剂。与基于喹唑啉的EGFR抑制剂相比，这些药物对EGFR T790M的效力高30至100倍，对野生型EGFR的效力低至100倍。它们在由EGFR T790M驱动的肺癌小鼠模型中也有效。共结晶研究揭示了这些试剂增强的效力和突变体选择性的结构基础。这些突变体选择性不可逆EGFR激酶抑制剂可能比基于喹唑啉的抑制剂在临床上更有效且耐受性更好。我们的发现表明，针对临床上重要的突变激酶的功能药理学筛选代表了一种强大的策略，可用于识别新型的突变选择性激酶抑制剂。

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  • 来源
    《Nature》 |2009年第7276期|1070-1074|共5页
  • 作者

    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. Jaenne;

  • 作者单位

    Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Biological Chemistry and Molecular Pharmacology,Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Biological Chemistry and Molecular Pharmacology,Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;

    The Barnett Institute of Chemical & Biological Analysis, Northeastern University, Boston, Massachusetts 02115, USA Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA;

    Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;

    The Barnett Institute of Chemical & Biological Analysis, Northeastern University, Boston, Massachusetts 02115, USA Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA;

    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Departmpnt of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston,Massachusetts 02115, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Biological Chemistry and Molecular Pharmacology,Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Biological Chemistry and Molecular Pharmacology,Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA;

    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA Departmpnt of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;

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