Abstract

Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-design targets. NUPR1 (or p8) is a multifunctional IDP , over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. In this seminar, we follow a three-part strategy. First, we show how p8 is an IDP , from an experimental and theoretical (primary structure) point of view. Second, we describe the interactions with its three natural partners and how the complexes formed are “fuzzy”. Finally, we describe our attempts to design drugs against p8, based on those partners. In a first attempt, 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. In a second attempt, we carried out “hypothesis-driven” experiments to identify other compounds against p8 (peptides and dendrimers). Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC , our studies prove the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.