Benzenesulphonamide inhibitors of the cytolytic protein perforin
Web of Science
AuthorSpicer, JA; Miller, CK; O'Connor, PD; Jose, J; Huttunen, KM; Jaiswal, JK; Denny, WA; Akhlaghi, H; Browne, KA; Trapani, JA
Source TitleBioorganic and Medicinal Chemistry Letters
PublisherPERGAMON-ELSEVIER SCIENCE LTD
University of Melbourne Author/sTrapani, Joseph
AffiliationSir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsSpicer, J. A., Miller, C. K., O'Connor, P. D., Jose, J., Huttunen, K. M., Jaiswal, J. K., Denny, W. A., Akhlaghi, H., Browne, K. A. & Trapani, J. A. (2017). Benzenesulphonamide inhibitors of the cytolytic protein perforin. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 27 (4), pp.1050-1054. https://doi.org/10.1016/j.bmcl.2016.12.057.
Access StatusOpen Access
The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo. The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility.
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