title: Development of peptidomimetic boronates as proteasome inhibitors.
abstract: Proteasome inhibition has emerged over the past decade as an effective therapeutic approach for the treatment of hematologic malignancies. It is a multicatalytic complex, whose proteolytic activity relies in three types of subunits: chymotrypsin-like (β5), trypsin-like (β2) and caspase-like (β1). Most important for the development of effective antitumor agents is the inhibition of the β5 subunits. In this context, the dipeptide boronate bortezomib (Velcade(®)) represents the first proteasome inhibitor approved by the FDA and the lead compound in drug discovery. This paper describes the synthesis and biological evaluation of a series of conformationally constrained pseudopeptide boronates (1-3) structurally related to bortezomib. The synthesized compounds showed a promising inhibitory profile by blocking primarily the chymotrypsin-like activity of the proteasome with Ki values in submicromolar/micromolar range. These compounds also resulted quite selective since no significant inhibition was recorded in the test against bovine pancreatic α-chymotrypsin. The obtained results were rationalized by means of docking experiments based on a model of the crystal structure of bortezomib bound to the yeast 20S proteasome providing essential insights for further optimization of this class of inhibitors.
authors: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy. nmicale@unime.it
authors: Nicola
authors: N
authors: Micale
authors: Roberta
authors: R
authors: Ettari
authors: Antonio
authors: A
authors: Lavecchia
authors: Carmen
authors: C
authors: Di Giovanni
authors: Kety
authors: K
authors: Scarbaci
authors: Valeria
authors: V
authors: Troiano
authors: Silvana
authors: S
authors: Grasso
authors: Ettore
authors: E
authors: Novellino
authors: Tanja
authors: T
authors: Schirmeister
authors: Maria
authors: M
authors: Zappalà
mesh_terms: D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001896:Boron Compounds; D057786:Peptidomimetics; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex