• M Raymond V Finlay, Mark Anderton, Susan Ashton, Peter Ballard, Paul A Bethel, Matthew R Box, Robert H Bradbury, Simon J Brown, Sam Butterworth, Andrew Campbell, Christopher Chorley, Nicola Colclough, Darren A E Cross, Gordon S Currie, Matthew Grist, Lorraine Hassall, George B Hill, Daniel James, Michael James, Paul Kemmitt, Teresa Klinowska, Gillian Lamont, Scott G Lamont, Nathaniel Martin, Heather L McFarland, Martine J Mellor, Jonathon P Orme, David Perkins, Paula Perkins, Graham Richmond, Peter Smith, Richard A Ward, Michael J Waring, David Whittaker, Stuart Wells, and Gail L Wrigley.
• Oncology Innovative Medicines, ‡Drug Safety and Metabolism, §Global Medicines Development, and ∥Discovery Sciences, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
• J. Med. Chem. 2014 Oct 23;57(20):8249-67.

AbstractEpidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

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