Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

• Published in: Nature (London) Vol. 462; no. 7276; pp. 1070 - 1074
• Main Authors: Yun, Cai-Hong, Chirieac, Lucian, Iacob, Roxana E, Padera, Robert, Zhou, Wenjun, Eck, Michael J, Engen, John R, Chen, Liang, Gray, Nathanael S, Jänne, Pasi A, Li, Danan, Capelletti, Marzia, Cortot, Alexis B, Ercan, Dalia, Wong, Kwok-Kin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.12.2009; Springer Nature; Nature Publishing Group
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Biological and medical sciences; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical synthesis; Crystal structure; Crystallization; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm - genetics; Drug therapy; Enzyme kinetics; Erlotinib; Gefitinib; General aspects; Health aspects; Humanities and Social Sciences; Inhibitors; Kinases; letter; Lung - drug effects; Lung cancer; Lung cancer, Non-small cell; Medical sciences; Mice; Models, Chemical; Models, Molecular; multidisciplinary; Multidisciplinary Sciences; Mutagenesis; Mutants; Mutation; Mutation - genetics; NIH 3T3 Cells; NMR; Nuclear magnetic resonance; Oncology, Experimental; Pharmacology. Drug treatments; Phosphorylation - drug effects; Pneumology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - toxicity; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Science; Science & Technology; Science & Technology - Other Topics; Science (multidisciplinary); Tumors of the respiratory system and mediastinum; CELL LUNG-CANCER; HKI-272; GEFITINIB; PAN-ERBB INHIBITOR; TYROSINE KINASE; MUTATION; IMATINIB; RESISTANCE; SENSITIVITY; NILOTINIB; Lung disease; Screening; Treatment resistance; Respiratory disease; Enzyme inhibitor; Bronchus disease; Malignant tumor; Mutation; non-small cell lung carcinoma; Epidermal growth factor receptor; Cancer
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08622

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.