title: The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
abstract: Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK. Electronic address: rebecca.newton@cruk.manchester.ac.uk.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Newton
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Bowler
authors.affiliation: Structural Biology Laboratory, Cancer Research UK London Research Institute, London, WC2A 3LY, England, UK.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Burns
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Chapman
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Fairweather
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Samantha J R
authors.initials: SJR
authors.lastname: Fritzl
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Goldberg
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Niall M
authors.initials: NM
authors.lastname: Hamilton
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Sarah V
authors.initials: SV
authors.lastname: Holt
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Gemma V
authors.initials: GV
authors.lastname: Hopkins
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Jones
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Jordan
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lyons
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: H
authors.initials: H
authors.lastname: Nikki March
authors.affiliation: Structural Biology Laboratory, Cancer Research UK London Research Institute, London, WC2A 3LY, England, UK; Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, Malet Street, London WC1E 7HX, England, UK.
authors.forename: Neil Q
authors.initials: NQ
authors.lastname: McDonald
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Maguire
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Mould
authors.affiliation: Structural Biology Laboratory, Cancer Research UK London Research Institute, London, WC2A 3LY, England, UK.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Purkiss
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Small
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Alexandra I J
authors.initials: AIJ
authors.lastname: Stowell
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Thomson
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Waddell
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Bohdan
authors.initials: B
authors.lastname: Waszkowycz
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Watson
authors.affiliation: Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Ogilvie
mesh_terms: D000818:Animals; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; C452423:vandetanib
keywords: Kinase; Quinazoline; RET