ArticleBiomolecules2021
Design of Inhibitors of the Intrinsically Disordered Protein NUPR1: Balance between Drug Affinity and Target Function.
Article in Biomolecules, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01692873 (Research for Prognostic and Predictive Biomarkers of Therapeutic Response in Pancreatic Tumors - PACAomics / IPC 2011-004), which is not on this map. Cited by 16 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Research for Prognostic and Predictive Biomarkers of Therapeutic Response in Pancreatic Tumors - PACAomics / IPC 2011-004
Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Histone H4K8 lactylation promotes glioblastoma progression by inducing NUPR1-mediated autophagosome‒lysosome fusion.Theranostics · 2026Article
- NUPR1 in breast cancer: mechanisms and potential applications.Frontiers in physiology · 2026Review
- The intrinsically disordered protein NUPR1 binds to phospholipids.Protein science : a publication of the Protein Society · 2025Article
- Current perspectives in drug targeting intrinsically disordered proteins and biomolecular condensates.BMC biology · 2025Review
- Deep Learning-Based Comparative Prediction and Functional Analysis of Intrinsically Disordered Regions in SARS-CoV-2.International journal of molecular sciences · 2025Article
- Development of an efficient NUPR1 inhibitor with anticancer activity.Scientific reports · 2024Article
- Genome, Metabolism, or Immunity: Which Is the Primary Decider of Pancreatic Cancer Fate through Non-Apoptotic Cell Death?Biomedicines · 2023Review
- Review
- Sustainable Biodegradable Biopolymer-Based Nanoparticles for Healthcare Applications.International journal of molecular sciences · 2023Review
- Deciphering the Binding of the Nuclear Localization Sequence of Myc Protein to the Nuclear Carrier Importin α3.International journal of molecular sciences · 2022Article
- Intrinsically Disordered Proteins: An Overview.International journal of molecular sciences · 2022Review
- Nanomedicines Meet Disordered Proteins: A Shift from Traditional Materials and Concepts to Innovative Polymers.Journal of personalized medicine · 2022Article
- Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization.Life (Basel, Switzerland) · 2022Review
- Article
- Characterization of intrinsically disordered regions in proteins informed by human genetic diversity.PLoS computational biology · 2022Article
- The Amazing World of IDPs in Human Diseases II.Biomolecules · 2022Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Intrinsically disordered proteins (IDPs) are emerging as attractive drug targets by virtue of their physiological ubiquity and their prevalence in various diseases, including cancer. NUPR1 is an IDP that localizes throughout the whole cell, and is involved in the development and progression of several tumors. We have previously repurposed trifluoperazine (TFP) as a drug targeting NUPR1 and, by using a ligand-based approach, designed the drug ZZW-115 starting from the TFP scaffold. Such derivative compound hinders the development of pancreatic ductal adenocarcinoma (PDAC) in mice, by hampering nuclear translocation of NUPR1. Aiming to further improve the activity of ZZW-115, here we have used an indirect drug design approach to modify its chemical features, by changing the substituent attached to the piperazine ring. As a result, we have synthesized a series of compounds based on the same chemical scaffold. Isothermal titration calorimetry (ITC) showed that, with the exception of the compound preserving the same chemical moiety at the end of the alkyl chain as ZZW-115, an increase of the length by a single methylene group (i.e., ethyl to propyl) significantly decreased the affinity towards NUPR1 measured in vitro, whereas maintaining the same length of the alkyl chain and adding heterocycles favored the binding affinity. However, small improvements of the compound affinity towards NUPR1, as measured by ITC, did not result in a corresponding improvement in their inhibitory properties and in cellulo functions, as proved by measuring three different biological effects: hindrance of the nuclear translocation of the protein, sensitization of cells against DNA damage mediated by NUPR1, and prevention of cancer cell growth. Our findings suggest that a delicate compromise between favoring ligand affinity and controlling protein function may be required to successfully design drugs against NUPR1, and likely other IDPs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.