title: Identification of a new series of amides as non-covalent proteasome inhibitors.
abstract: Proteasome inhibition has emerged as an important therapeutic strategy for the treatment of multiple myeloma (MM) and some forms of lymphoma, with potential application in other types of cancers. 20S proteasome consists of three different catalytic activities known as chymotrypsin-like (ChT-L), trypsin-like (T-L), and, post-glutamyl peptide hydrolyzing (PGPH) or caspase-like (C-L), which are located respectively on the β5, β2, and β1 subunits of each heptameric β rings. Currently a wide number of covalent proteasome inhibitors are reported in literature; however, the less widely investigated non-covalent inhibitors might be a promising alternative to employ in therapy, because of the lack of all drawbacks and side-effects related to irreversible inhibition. In the present work we identified a series of amides, two of which (1b and 1f) are good candidates to non-covalent inhibition of the chymotrypsin-like activity of the β5 proteasome subunit. The non-covalent binding mode was corroborated by docking simulations of the most active inhibitors 1b, 1f and 2h into the yeast 20S proteasome crystal structure.
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Kety
authors.initials: K
authors.lastname: Scarbaci
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Troiano
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. Electronic address: roberta.ettari@unimi.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Di Giovanni
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cerchia
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, D-55099 Mainz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Zappalà
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000577:Amides; D061988:Proteasome Inhibitors
keywords: Amides; Docking studies; Non-covalent inhibitors; Proteasome inhibitors