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    Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade.

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    Authors
    Watson, Amanda J
    Hopkins, Gemma V
    Hitchin, Samantha
    Begum, Habiba
    Jones, Stuart
    Jordan, Allan M
    Holt, Sarah V
    March, H Nikki
    Newton, Rebecca
    Small, Helen F
    Stowell, Alexandra I J
    Waddell, Ian D
    Waszkowycz, Bohdan
    Ogilvie, Donald J
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    Affiliation
    Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester
    Issue Date
    2016
    
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    Abstract
    RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments. In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series.  Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile.
    Citation
    Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade. 2016, 5:1005 F1000Res
    Journal
    F1000Research
    URI
    http://hdl.handle.net/10541/618470
    DOI
    10.12688/f1000research.8724.1
    PubMed ID
    27429741
    Type
    Article
    Language
    en
    ISSN
    2046-1402
    ae974a485f413a2113503eed53cd6c53
    10.12688/f1000research.8724.1
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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