Journal of Medicinal Chemistry p. 8249 - 8267 (2014)
Update date:2022-08-05
Topics:
Finlay, M. Raymond V.
Anderton, Mark
Ashton, Susan
Ballard, Peter
Bethel, Paul A.
Box, Matthew R.
Bradbury, Robert H.
Brown, Simon J.
Butterworth, Sam
Campbell, Andrew
Chorley, Christopher
Colclough, Nicola
Cross, Darren A. E.
Currie, Gordon S.
Grist, Matthew
Hassall, Lorraine
Hill, George B.
James, Daniel
James, Michael
Kemmitt, Paul
Klinowska, Teresa
Lamont, Gillian
Lamont, Scott G.
Martin, Nathaniel
McFarland, Heather L.
Mellor, Martine J.
Orme, Jonathon P.
Perkins, David
Perkins, Paula
Richmond, Graham
Smith, Peter
Ward, Richard A.
Waring, Michael J.
Whittaker, David
Wells, Stuart
Wrigley, Gail L.
Epidermal 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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