title: Inhibition of the pore-forming protein perforin by a series of aryl-substituted isobenzofuran-1(3H)-ones.
abstract: An aryl-substituted isobenzofuran-1(3H)-one lead compound was identified from a high throughput screen designed to find inhibitors of the lymphocyte pore-forming protein perforin. A series of analogs were then designed and prepared, exploring structure-activity relationships through variation of 2-thioxoimidazolidin-4-one and furan subunits on an isobenzofuranone core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 natural killer effector cells was determined. Several compounds showed excellent activity at concentrations that were non-toxic to the killer cells. This series represents a significant improvement on previous classes of compounds, being substantially more potent and largely retaining activity in the presence of serum.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. j.spicer@auckland.ac.nz
authors.forename: Julie A
authors.initials: JA
authors.lastname: Spicer
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
authors.forename: Christian K
authors.initials: CK
authors.lastname: Miller
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Annette
authors.initials: A
authors.lastname: Ciccone
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Browne
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
mesh_terms: D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects; D054353:Perforin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001572:Benzofurans; D007166:Immunosuppressive Agents; D054353:Perforin