title: 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.
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.
authors.affiliation: Oncology Innovative Medicines, ‡Drug Safety and Metabolism, §Global Medicines Development, and ∥Discovery Sciences, AstraZeneca , Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
authors.forename: M Raymond V
authors.initials: MR
authors.lastname: Finlay
authors.forename: Mark
authors.initials: M
authors.lastname: Anderton
authors.forename: Susan
authors.initials: S
authors.lastname: Ashton
authors.forename: Peter
authors.initials: P
authors.lastname: Ballard
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bethel
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Box
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bradbury
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Sam
authors.initials: S
authors.lastname: Butterworth
authors.forename: Andrew
authors.initials: A
authors.lastname: Campbell
authors.forename: Christopher
authors.initials: C
authors.lastname: Chorley
authors.forename: Nicola
authors.initials: N
authors.lastname: Colclough
authors.forename: Darren A E
authors.initials: DA
authors.lastname: Cross
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Currie
authors.forename: Matthew
authors.initials: M
authors.lastname: Grist
authors.forename: Lorraine
authors.initials: L
authors.lastname: Hassall
authors.forename: George B
authors.initials: GB
authors.lastname: Hill
authors.forename: Daniel
authors.initials: D
authors.lastname: James
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.forename: Paul
authors.initials: P
authors.lastname: Kemmitt
authors.forename: Teresa
authors.initials: T
authors.lastname: Klinowska
authors.forename: Gillian
authors.initials: G
authors.lastname: Lamont
authors.forename: Scott G
authors.initials: SG
authors.lastname: Lamont
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Martin
authors.forename: Heather L
authors.initials: HL
authors.lastname: McFarland
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Mellor
authors.forename: Jonathon P
authors.initials: JP
authors.lastname: Orme
authors.forename: David
authors.initials: D
authors.lastname: Perkins
authors.forename: Paula
authors.initials: P
authors.lastname: Perkins
authors.forename: Graham
authors.initials: G
authors.lastname: Richmond
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ward
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waring
authors.forename: David
authors.initials: D
authors.lastname: Whittaker
authors.forename: Stuart
authors.initials: S
authors.lastname: Wells
authors.forename: Gail L
authors.initials: GL
authors.lastname: Wrigley
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D060326:Chemistry Techniques, Synthetic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011919:Rats, Inbred Strains; D023041:Xenograft Model Antitumor Assays; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines