DALILA BOI

PhD Graduate

PhD program:: XXXIV


supervisor: Giulia Guarguaglini
advisor: Alessandro Paiardini
co-supervisor: Alessandro Paiardini

Thesis title: Protein-protein interaction inhibitors as an innovative approach to target the Aurora-A/N-Myc complex in neuroblastoma

Neuroblastoma is the most common extracranial solid tumour in childhood, accounting for ~10% of all infant cancers. Although several signalling pathways and genomic features associate with neuroblastoma progression, the amplification of the MYCN gene, coding for the N-Myc transcription factor, correlates with high aggressiveness and poor outcome. MYCN-amplified (MNA) neuroblastoma cells are addicted to the transcriptional profile ensured by N-Myc, which, due to its disordered conformation, is considered an undruggable target. The recent evidence that the Aurora-A kinase interacts with N-Myc, protecting it from proteasome mediated degradation in MNA neuroblastoma cells, disclosed a new strategy of intervention. Indeed, targeting the Aurora-A/N-Myc complex turned out to be a good strategy against high-risk neuroblastoma. In particular, a sub-class of ATP-competitive inhibitors of the kinase, i.e., conformational disrupting (CD) molecules, are able to induce a drastic rearrangement of the Aurora-A structure, which impairs N-Myc binding and causes the decrease of N-Myc protein levels. In this thesis, I investigated new approaches to inhibit the interaction between Aurora-A and N-Myc via a two-pronged strategy: i) identify, among already known Aurora-A kinase inhibitors, new compounds affecting the conformation of the kinase and ii) develop protein-protein interaction inhibitors of the complex, using a peptide-based scaffold. Using Bioinformatics approaches, we identified already known Aurora-A kinase inhibitors, which could act as CD molecules. Then, Surface Plasmon Resonance (SPR) experiments were carried out to assess the ability of such compounds to hamper the binding of Aurora-A and N-Myc in vitro. We then confirmed the ability of the most promising inhibitor, PHA-680626, to impair the Aurora-A/N-Myc interaction in MYCN overexpressing cell lines. Moreover, we observed a decrease in N-Myc protein levels and the appearance of cell death markers in a MNA neuroblastoma cell line. Regarding the second part of this study, we assessed the ability of Protein Kinase A Inhibitor (PKI)-based peptide inhibitors, in silico modified to allow the binding with Aurora-A, to impair the Aurora-A/N-Myc complex in MYCN overexpressing cells. Therefore, the molecules identified in this study expand the repertoire of in neuroblastoma.

Research products

11573/1681779 - 2023 - When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases
Boi, Dalila; Rubini, Elisabetta; Breccia, Sara; Guarguaglini, Giulia; Paiardini, Alessandro - 01a Articolo in rivista
paper: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. - - issn: 1661-6596 - wos: WOS:000947160200001 (3) - scopus: 2-s2.0-85149819415 (3)

11573/1625113 - 2022 - Prediction and modeling of protein–protein interactions using “Spotted” peptides with a template-based approach
Gasbarri, C.; Rosignoli, S.; Janson, G.; Boi, D.; Paiardini, A. - 01a Articolo in rivista
paper: BIOMOLECULES (Basel: MDPI) pp. 201- - issn: 2218-273X - wos: WOS:000763712100001 (1) - scopus: 2-s2.0-85123311952 (1)

11573/1584599 - 2022 - Cytosolic localization and in vitro assembly of human de novo thymidylate synthesis complex
Spizzichino, Sharon; Boi, Dalila; Boumis, Giovanna; Lucchi, Roberta; Liberati, Francesca Romana; Capelli, Davide; Montanari, Roberta; Pochetti, Giorgio; Piacentini, Roberta; Parisi, Giacomo; Paone, Alessio; Rinaldo, Serena; Contestabile, Roberto; Tramonti, Angela; Paiardini, Alessandro; Giardina, Giorgio; Cutruzzolà, Francesca - 01a Articolo in rivista
paper: THE FEBS JOURNAL (Blackwell Pub., Oxford, UK) pp. 1625-1649 - issn: 1742-464X - wos: WOS:000717476400001 (1) - scopus: 2-s2.0-85118844105 (2)

11573/1615167 - 2021 - Pha-680626 is an effective inhibitor of the interaction between aurora-a and n-myc
Boi, D.; Souvalidou, F.; Capelli, D.; Polverino, F.; Marini, G.; Montanari, R.; Pochetti, G.; Tramonti, A.; Contestabile, R.; Trisciuoglio, D.; Carpinelli, P.; Ascanelli, C.; Lindon, C.; De Leo, A.; Saviano, M.; Di Santo, R.; Costi, R.; Guarguaglini, G.; Paiardini, A. - 01a Articolo in rivista
paper: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. 13122- - issn: 1661-6596 - wos: WOS:000735123900001 (9) - scopus: 2-s2.0-85120777012 (10)

11573/1574100 - 2021 - Nuclear localisation of Aurora-A: its regulation and significance for Aurora-A functions in cancer
Naso, F. D.; Boi, D.; Ascanelli, C.; Pamfil, G.; Lindon, C.; Paiardini, A.; Guarguaglini, G. - 01g Articolo di rassegna (Review)
paper: ONCOGENE (Macmillan Magazines Limited:Porters South Crinian Street, London N1 9XW United Kingdom:011 44 207 8334000, 011 44 171 8434982, Fax: 011 44 207 812358) pp. 3917-3928 - issn: 0950-9232 - wos: WOS:000650165600001 (24) - scopus: 2-s2.0-85105789689 (24)

11573/1553985 - 2021 - Cytosolic localization and in vitro assembly of human de novo thymidylate synthesis complex
Spizzichino, Sharon; Boi, Dalila; Boumis, Giovanna; Tramonti, Angela; Paiardini, Alessandro; Contestabile, Roberto; Pochetti, Giorgio; Rinaldo, Serena; Paone, Alessio; Giardina, Giorgio; Cutruzzola', Francesca - 04d Abstract in atti di convegno
conference: 16th SIBBM Seminar Frontiers in Molecular Biology Frontiers in metabolic research (online)
book: 16th SIBBM Seminar Frontiers in Molecular Biology Frontiers in metabolic research Abstracts - ()

11573/1276564 - 2019 - Isolation of a complex formed between acinetobacter baumannii hema and heml, key enzymes of tetrapyrroles biosynthesis
Nardella, Caterina; Boi, Dalila; Di Salvo, Martino L; Barile, Anna; Stetefeld, Jörg; Tramonti, Angela; Contestabile, Roberto - 01a Articolo in rivista
paper: FRONTIERS IN MOLECULAR BIOSCIENCES (Lausanne : Frontiers Media S.A., 2014-) pp. - - issn: 2296-889X - wos: WOS:000460605400001 (8) - scopus: 2-s2.0-85064466792 (10)

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