Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

Neira, J.L. ; Bintz, J. ; Arruebo, M. ; Rizzuti, B. ; Bonacci, T. ; Vega, S. ; Lanas, A. (Universidad de Zaragoza) ; Velázquez-Campoy, A. (Universidad de Zaragoza) ; Iovanna, J.L. ; Abián, O. (Universidad de Zaragoza)

Resumen: Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ''fuzzy'' interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.

Idioma: Inglés

DOI: 10.1038/srep39732

Año: 2017

Publicado en: Scientific reports 7 (2017), [15 pp.]
ISSN: 2045-2322

Factor impacto JCR: 4.122 (2017)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 12 / 64 = 0.188 (2017) - Q1 - T1

Factor impacto SCIMAGO: 1.533 - Multidisciplinary (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/B01
Financiación: info:eu-repo/grantAgreement/ES/DGA/B89
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI10-00186
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI11-02578
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI15-00663
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2015-64445-R

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)