학술논문
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.
Document Type
Academic Journal
Author
Finlay MR; Oncology Innovative Medicines, ‡Drug Safety and Metabolism, §Global Medicines Development, and ∥Discovery Sciences, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.; Anderton M; Ashton S; Ballard P; Bethel PA; Box MR; Bradbury RH; Brown SJ; Butterworth S; Campbell A; Chorley C; Colclough N; Cross DA; Currie GS; Grist M; Hassall L; Hill GB; James D; James M; Kemmitt P; Klinowska T; Lamont G; Lamont SG; Martin N; McFarland HL; Mellor MJ; Orme JP; Perkins D; Perkins P; Richmond G; Smith P; Ward RA; Waring MJ; Whittaker D; Wells S; Wrigley GL
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
Subject
Language
English
Abstract
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.