Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.
Zhou, Wenjun 1,2,10; Ercan, Dalia 3,4,10; Chen, Liang 3,4,10; Yun, Cai-Hong 1,2,10; Li, Danan 3,4; Capelletti, Marzia 3,4; Cortot, Alexis B. 3,4; Chirieac, Lucian 5; Iacob, Roxana E. 6,7; Padera, Robert 5; Engen, John R. 6,7; Wong, Kwok-Kin 3,4,8,9; Eck, Michael J. 1,2; Gray, Nathanael S. 1,2,*; Janne, Pasi A. 3,4,8,*
[Letter] Nature. 462(7276):1070-1074, December 24, 2009.

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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 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.

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