Data di Pubblicazione:
2013
Citazione:
Development of Peptidomimetic Boronates as Proteasome Inhibitors / N. Micale, R. Ettari, A. Lavecchia, C. Di Giovanni, K. Scarbaci, V. Troiano, S. Grasso, E. Novellino, T. Schirmeister, M. Zappalà. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 64(2013), pp. 23-34. [10.1016/j.ejmech.2013.03.032]
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.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
N. Micale, R. Ettari, A. Lavecchia, C. Di Giovanni, K. Scarbaci, V. Troiano, S. Grasso, E. Novellino, T. Schirmeister, M. Zappalà
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