title: Anilinoquinazoline inhibitors of the RET kinase domain-Elaboration of the 7-position.
abstract: We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Jordan
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Habiba
authors.initials: H
authors.lastname: Begum
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Fairweather
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Fritzl
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Kristin
authors.initials: K
authors.lastname: Goldberg
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Gemma V
authors.initials: GV
authors.lastname: Hopkins
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Niall M
authors.initials: NM
authors.lastname: Hamilton
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lyons
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: H Nikki
authors.initials: HN
authors.lastname: March
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Newton
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Small
authors.affiliation: Medicinial Chemistry, SAI Life Sciences, Ltd, Pune, India.
authors.forename: Swamy
authors.initials: S
authors.lastname: Vishwanath
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Waddell
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Watson
authors.affiliation: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Ogilvie
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret
keywords: Hepatocyte stability; Kinase inhibitor; Lung cancer; RET receptor; Targeted therapy