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

    Newton, R. and Bowler, K.A. and Burns, E.M. and Chapman, P.J. and Fairweather, E.E. and Fritzl, S.J.R. and Goldberg, K.M. and Hamilton, N.M. and Holt, S.V. and Hopkins, G.V. and Jones, S.D. and Jordan, A.M. and Lyons, A.J. and Nikki March, H. and McDonald, Neil Q. and Maguire, L.A. and Mould, D.P. and Purkiss, A.G. and Small, H.F. and Stowell, A.I.J. and Thomson, G.J. and Waddell, I.D. and Waszkowycz, B. and Watson, A.J. and Ogilvie, D.J. (2016) The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. European Journal of Medicinal Chemistry 112 , pp. 20-32. ISSN 0223-5234.

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    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.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): Kinase, Quinazoline, RET
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 01 Mar 2016 12:14
    Last Modified: 28 Sep 2018 13:08
    URI: http://eprints.bbk.ac.uk/id/eprint/14530

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