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    Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1.

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    Authors
    Mould, Daniel P
    Bremberg, U
    Jordan, Allan M
    Geitmann, M
    McGonagle, Alison E
    Somervaille, Tim C P
    Spencer, Gary J
    Ogilvie, Donald J
    Affiliation
    Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX,
    Issue Date
    2017-10-15
    
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    Abstract
    As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22nM and a biochemical IC50 of 57nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping asa method to develop structurally diverse, potent inhibitors of LSD1.
    Citation
    Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1. 2017, 27 (20):4755-4759 Bioorg Med Chem Lett
    Journal
    Bioorganic & Medicinal Chemistry Letters
    URI
    http://hdl.handle.net/10541/620610
    DOI
    10.1016/j.bmcl.2017.08.052
    PubMed ID
    28927796
    Type
    Article
    Language
    en
    ISSN
    1464-3405
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.bmcl.2017.08.052
    Scopus Count
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    All Paterson Institute for Cancer Research

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