title: Diarylthiophenes as inhibitors of the pore-forming protein perforin.
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.
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; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO 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: William A
authors.initials: WA
authors.lastname: Denny
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Jagdish K
authors.initials: JK
authors.lastname: Jaiswal
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Victoria 3002, Australia.
authors.forename: Annette
authors.initials: A
authors.lastname: Ciccone
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Victoria 3002, Australia.
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Browne
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Victoria 3002, 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
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
mesh_terms: D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D054353:Perforin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C475670:2(3H)-benzofuranone; D001572:Benzofurans; D013876:Thiophenes; D054353:Perforin
keywords: Bioisostere; Diarylthiophene; Immunosuppressant; Perforin; Perforin inhibitor