2. Academic Validation
  3. Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors

Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors

  • Eur J Med Chem. 2014 Aug 18:83:1-14. doi: 10.1016/j.ejmech.2014.06.017.
Valeria Troiano 1,  Kety Scarbaci 1,  Roberta Ettari 2,  Nicola Micale 1,  Carmen Cerchia 3,  Andrea Pinto 4,  Tanja Schirmeister 5,  Ettore Novellino 3,  Silvana Grasso 6,  Antonio Lavecchia 7,  Maria Zappalà 1
Affiliations

Affiliations

  • 1 Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
  • 2 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. Electronic address: [email protected].
  • 3 Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
  • 4 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
  • 5 Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, D-55099 Mainz, Germany.
  • 6 Dipartimento di Scienze Chimiche, Università degli Studi di Messina, Via F. Stagno D'Alcontres 31, 98166 Messina, Italy.
  • 7 Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. Electronic address: [email protected].
PMID: 24946214 DOI: 10.1016/j.ejmech.2014.06.017
Abstract

A new series of pseudopeptide boronate Proteasome inhibitors (2-3) was developed, through optimization of our previously described analogs of bortezomib, bearing a bicyclic 1,6-naphthyridin-5(6H)-one scaffold as P3 fragment (1). The biological evaluation on human 20S Proteasome displayed a promising inhibition profile, especially for compounds bearing a P2 ethylene fragment, which exhibited Ki values in the nanomolar range for the ChT-L activity (e.g. 2a, Ki = 0.057 μM) and considerable selectivity for Proteasome over bovine pancreatic α-chymotrypsin. Docking experiments into the yeast 20S Proteasome revealed that the ligands are accommodated predominantly into the ChT-L site and that they covalently bind to the active site threonine residue via boron atom. Within the cellular assays performed against a 60 Cancer cell line panel, compounds 3e and 3f demonstrated also good antiproliferative activity and compound 3f emerged as promising lead compound for the development of Anticancer agents targeting melanoma and non-small cell lung Cancer.

Keywords

Docking studies; Peptidomimetic boronates; Proteasome inhibitors.

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