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    The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.

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    Authors
    Newton, Rebecca
    Bowler, K
    Burns, E
    Chapman, Philip J
    Fairweather, Emma E
    Fritzl, Samantha J R
    Goldberg, Kristin M
    Hamilton, Niall M
    Holt, Sarah V
    Hopkins, Gemma V
    Jones, Stuart D
    Jordan, Allan M
    Lyons, Amanda J
    March, H Nikki
    McDonald, N
    Maguire, Laura A
    Mould, Daniel P
    Purkiss, A
    Small, Helen F
    Stowell, Alexandra I J
    Thomson, Graeme J
    Waddell, Ian D
    Waszkowycz, Bohdan
    Watson, Amanda J
    Ogilvie, Donald J
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    Affiliation
    Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX
    Issue Date
    2016-04-13
    
    Metadata
    Show full item record
    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.
    Citation
    The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. 2016, 112:20-32 Eur J Med Chem
    Journal
    European Journal of Medicinal Chemistry
    URI
    http://hdl.handle.net/10541/604149
    DOI
    10.1016/j.ejmech.2016.01.039
    PubMed ID
    26874741
    Type
    Article
    Language
    en
    ISSN
    1768-3254
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ejmech.2016.01.039
    Scopus Count
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    All Paterson Institute for Cancer Research

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