Please use this identifier to cite or link to this item:
Title: Computational techniques are valuable tools for the discovery of protein-protein interaction inhibitors: the 14-3-3s case
Authors: Corradi, V
Mancini, M
Carlomagno, T
Sanfelice, D
Mori, M
Vignaroli, Giulia
Falchi, F
Manetti, Fabrizio 
Botta, Maurizio 
Botta, Maurizio 
Keywords: 14-3-3; Leukemia; Molecular modeling; Protein-protein interaction; T315I
Issue Date: 2011
Project: None 
Targeting the binding site of 14-3-3 proteins lets the release of partner proteins involved in cell cycle progression, apoptosis, cytoskeletal rearrangement and transcriptional regulation and may therefore be regarded as an alternative strategy to integrate conventional therapeutic approaches against cancer. In the present work, we report the identification of two new small molecule inhibitors of 14-3-3σ/c-Abl protein-protein interaction (BV01 and BV101) discovered by means of computational methods. The most interesting compound (BV01) showed a lethal dose (LD 50) in the low micromolar range against Ba/F3 murine cell lines expressing the Imatinib (IM)-sensitive wild type Bcr-Abl construct and the IM-resistant Bcr-Abl mutation T315I. BV01 interaction with 14-3-3σ was demonstrated by NMR studies and elucidated by docking. It blocked the binding domain of 14-3-3σ, hence promoting the release of the partner protein c-Abl (the one not involved in Bcr rearrangement), and its translocation to both the nuclear compartment and mitochondrial membranes to induce a pro-apoptotic response. Our results advance BV01 as a confirmed hit compound capable of eliciting apoptotic death of Bcr-Abl-expressing cells by interfering with 14-3-3σ/c-Abl protein-protein interaction.
ISSN: 0960-894X
DOI: 10.1016/j.bmcl.2011.09.011
Appears in Collections:Publications

Show full item record

Google ScholarTM



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.