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Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma
José L Neira1,2, Jennifer Bintz3, María Arruebo4,5
1Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Edificio Torregaitán, Avda. del Ferrocarril s/n, 03202 Elche, Alicante, Spain.
Abstract:
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.
Insights
Researchers identified FDA-approved compounds targeting the intrinsically disordered protein NUPR1, crucial in pancreatic cancer. These drugs halt cancer growth and migration, with one compound completely stopping tumor development in mice.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Intrinsically disordered proteins (IDPs) play vital roles in cellular signaling and regulation.
- IDPs are implicated in various human diseases and represent promising drug targets.
- Nuclear protein 1 (NUPR1) is an IDP overexpressed in pancreatic ductal adenocarcinoma (PDAC), contributing to its development.
Purpose of the Study:
- To screen FDA-approved compounds for potential drug candidates targeting the intrinsically disordered protein NUPR1.
- To investigate the interaction between selected compounds and NUPR1, and their effects on PDAC cells.
- To evaluate the therapeutic potential of NUPR1-targeting compounds in preclinical models of pancreatic cancer.
Main Methods:
- Screening of 1120 FDA-approved compounds against NUPR1.
- Experimental and simulation techniques to characterize compound-NUPR1 interactions.
- In vitro cell-based assays and in vivo xenograft models using PDAC cells.
Main Results:
- Fifteen candidate compounds were identified that bind to NUPR1 while maintaining its disordered state.
- All tested compounds induced cell-growth arrest, senescence, reduced migration, and decreased chemoresistance in PDAC cells.
- The most effective compound demonstrated complete inhibition of tumor development in vivo.
Conclusions:
- Targeting intrinsically disordered proteins like NUPR1 with small molecules is feasible.
- Compounds targeting NUPR1 exhibit significant preclinical efficacy against pancreatic ductal adenocarcinoma.
- This study validates the 'fuzzy' binding interface of IDPs as a druggable target for cancer therapy.
