Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor
| Autor: | Peter Ballard, Michael James, Daniel S. James, Peter D. Smith, Simon J. Brown, M. Raymond V. Finlay, Michael J. Waring, Paula Perkins, Andrew D. Campbell, Heather L. McFarland, David Perkins, Gordon S. Currie, Gillian M. Lamont, Graham Richmond, Matthew R. Box, David Whittaker, Mark J. Anderton, Richard A. Ward, Teresa Klinowska, Scott G. Lamont, Nicola Colclough, Stuart L. Wells, Darren Cross, Gail L. Wrigley, George B. Hill, Nathaniel G. Martin, Paul D. Kemmitt, Susan Ashton, Lorraine A. Hassall, Paul A. Bethel, Robert Hugh Bradbury, Sam Butterworth, Christopher G. Chorley, Martine J. Mellor, Matthew Grist, Jonathon P. Orme |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Lung Neoplasms Antineoplastic Agents Drug resistance Chemistry Techniques Synthetic Pharmacology medicine.disease_cause T790M Inhibitory Concentration 50 Mice Carcinoma Non-Small-Cell Lung Drug Discovery medicine Animals Humans Rociletinib Epidermal growth factor receptor Lung cancer Protein Kinase Inhibitors EGFR inhibitors Mutation Acrylamides Aniline Compounds biology Wild type Rats Inbred Strains Middle Aged medicine.disease Xenograft Model Antitumor Assays respiratory tract diseases ErbB Receptors Drug Resistance Neoplasm biology.protein Molecular Medicine Female |
| Zdroj: | Journal of medicinal chemistry. 57(20) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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