Identification of a new series of amides as non-covalent proteasome inhibitors

Autoren

Kety Scarbaci
Valeria Troiano
Nicola Micale
Roberta Ettari
Lucia Tamborini
Carmen Di Giovanni
Carmen Cerchia
Silvana Grasso
Ettore Novellino
Tanja Schirmeister
Antonio Lavecchia
Maria Zappalà

DOI

10.1016/j.ejmech.2014.01.022

ISSN

0223-5234

Zeitschrift

European Journal of Medicinal Chemistry

Sprache

en

Paginierung

1 - 9

Datum der Veröffentlichung

2014

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.ejmech.2014.01.022

Datum der Datenerfassung

2018

Titel

Identification of a new series of amides as non-covalent proteasome inhibitors

Ausgabe der Zeitschrift

76

Data source: Crossref

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.

Addresses

Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.

Autoren

Kety Scarbaci
Valeria Troiano
Nicola Micale
Roberta Ettari
Lucia Tamborini
Carmen Di Giovanni
Carmen Cerchia
Silvana Grasso
Ettore Novellino
Tanja Schirmeister
Antonio Lavecchia
Maria Zappalà

DOI

10.1016/j.ejmech.2014.01.022

eISSN

1768-3254

Externe Identifier

PubMed Identifier: 24561716

Open access

false

ISSN

0223-5234

Zeitschrift

European journal of medicinal chemistry

Schlüsselwörter

Humans
Amides
Magnetic Resonance Spectroscopy
Proteasome Inhibitors
Molecular Docking Simulation

Sprache

eng

Medium

Print-Electronic

Online publication date

2014

Paginierung

1 - 9

Datum der Veröffentlichung

2014

Status

Published

Datum der Datenerfassung

2014

Titel

Identification of a new series of amides as non-covalent proteasome inhibitors.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

76

Data source: Europe PubMed Central

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.

Date of acceptance

2014

Autoren

Kety Scarbaci
Valeria Troiano
Nicola Micale
Roberta Ettari
Lucia Tamborini
Carmen Di Giovanni
Carmen Cerchia
Silvana Grasso
Ettore Novellino
Tanja Schirmeister
Antonio Lavecchia
Maria Zappalà

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/24561716

DOI

10.1016/j.ejmech.2014.01.022

eISSN

1768-3254

Zeitschrift

Eur J Med Chem

Schlüsselwörter

Amides
Docking studies
Non-covalent inhibitors
Proteasome inhibitors
Amides
Humans
Magnetic Resonance Spectroscopy
Molecular Docking Simulation
Proteasome Inhibitors

Sprache

eng

Country

France

Paginierung

1 - 9

PII

S0223-5234(14)00053-1

Datum der Veröffentlichung

2014

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2014

Titel

Identification of a new series of amides as non-covalent proteasome inhibitors.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

76

Data source: PubMed

Identification of a new series of amides as non-covalent proteasome inhibitors

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