期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep39732
关键词
-
资金
- La Ligue Contre le Cancer
- INCa
- Canceropole PACA
- DGOS (labellisation SIRIC)
- INSERM
- Miguel Servet Program from Instituto de Salud Carlos III [CPII13/00017]
- Fondo de Investigaciones Sanitarias [PI10/00186, PI15/00663, PI11/02578]
- Spanish Ministry of Economy and Competitiveness [BFU2013-47064-P, CTQ2015-64445-R]
- Diputacion General de Aragon [B89, B01]
- Generalitat Valenciana [018/2013]
- Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd)
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 PDACderived 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据