Diarylthiophenes as inhibitors of the pore-forming protein perforin

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    Author
    Miller, CK; Huttunen, KM; Denny, WA; Jaiswal, JK; Ciccone, A; Browne, KA; Trapani, JA; Spicer, JA
    Date
    2016-01-15
    Source Title
    Bioorganic and Medicinal Chemistry Letters
    Publisher
    PERGAMON-ELSEVIER SCIENCE LTD
    University of Melbourne Author/s
    Trapani, Joseph
    Affiliation
    Sir Peter MacCallum Department of Oncology
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    Document Type
    Journal Article
    Citations
    Miller, C. K., Huttunen, K. M., Denny, W. A., Jaiswal, J. K., Ciccone, A., Browne, K. A., Trapani, J. A. & Spicer, J. A. (2016). Diarylthiophenes as inhibitors of the pore-forming protein perforin. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 26 (2), pp.355-360. https://doi.org/10.1016/j.bmcl.2015.12.003.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/258083
    DOI
    10.1016/j.bmcl.2015.12.003
    Abstract
    Evolution from a furan-containing high-throughput screen (HTS) hit (1) resulted in isobenzofuran-1(3H)-one (2) as a potent inhibitor of the function of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 NK cells. In the current study, structure-activity relationship (SAR) development towards a novel series of diarylthiophene analogues has continued through the use of substituted-benzene and -pyridyl moieties as bioisosteres for 2-thioxoimidazolidin-4-one (A) on a thiophene (B) -isobenzofuranone (C) scaffold. The resulting compounds were tested for their ability to inhibit perforin lytic activity in vitro. Carboxamide (23) shows a 4-fold increase over (2) in lytic activity against isolated perforin and provides good rationale for continued development within this class.

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