title: Nonpeptidic Selective Inhibitors of the Chymotrypsin-Like (β5 i) Subunit of the Immunoproteasome.
abstract: Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide-based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin-like (β5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the β5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell-based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as β5i-selective probes for possible application in noncancer diseases related to the immunoproteasome.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Gobec
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors.forename: Damijan
authors.initials: D
authors.lastname: Knez
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors.forename: Matej
authors.initials: M
authors.lastname: Živec
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Konc
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia.
authors.forename: Samo
authors.initials: S
authors.lastname: Lešnik
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia.
authors.forename: Mitja
authors.initials: M
authors.lastname: Ogrizek
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors.forename: Aleš
authors.initials: A
authors.lastname: Obreza
authors.affiliation: Department of Environmental Sciences, Jožef Stefan Institute, Jamova 39, 1000, Ljubljana, Slovenia.
authors.forename: Dušan
authors.initials: D
authors.lastname: Žigon
authors.affiliation: Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, 6000, Koper, Slovenia.
authors.forename: Dušanka
authors.initials: D
authors.lastname: Janežič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
authors.forename: Irena
authors.initials: I
authors.lastname: Mlinarič-Raščan
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia. stanislav.gobec@ffa.uni-lj.si.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D046988:Proteasome Endopeptidase Complex
keywords: drug design; immunoproteasome; inhibitors; irreversible inhibition; small-molecule inhibitors