title: Benzenesulphonamide inhibitors of the cytolytic protein perforin.
abstract: 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.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand. Electronic address: j.spicer@auckland.ac.nz.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Spicer
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Miller
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: O'Connor
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
authors.forename: Jiney
authors.initials: J
authors.lastname: Jose
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
authors.forename: Jagdish K
authors.initials: JK
authors.lastname: Jaiswal
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia.
authors.forename: Hedieh
authors.initials: H
authors.lastname: Akhlaghi
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia.
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Browne
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D054353:Perforin / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D007166:Immunosuppressive Agents; D054353:Perforin; D013449:Sulfonamides; D000096926:Benzenesulfonamides
keywords: Benzenesulphonamide; Bioisostere; Immunosuppressant; Perforin; Perforin inhibitor