title: Computational techniques are valuable tools for the discovery of protein-protein interaction inhibitors: the 14-3-3σ case.
abstract: 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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, University of Siena,Via Alcide de Gasperi 2, I-53100 Siena, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Corradi
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
authors.forename: Teresa
authors.initials: T
authors.lastname: Carlomagno
authors.forename: Domenico
authors.initials: D
authors.lastname: Sanfelice
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.forename: Giulia
authors.initials: G
authors.lastname: Vignaroli
authors.forename: Federico
authors.initials: F
authors.lastname: Falchi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D015195:Drug Design; D005092:Exonucleases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D005095:Exoribonucleases; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D011485:Protein Binding / Q000187:drug effects*; D025941:Protein Interaction Mapping; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D054852:Small Molecule Libraries; D016315:Proto-Oncogene Proteins c-abl; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human