Evidence map›Paper›PMID 40957952›Full record

ArticleNature chemistry2025

Tumour-specific STING agonist synthesis via a two-component prodrug system.

Nai-Shu Hsu, Cong Tang, Raquel V Mendes, Carlos Labão-Almeida, Caio V Dos Reis, Ana R Coelho, Marta C Marques, Mar Cabeza Cabrerizo, Roman Misteli, Timothy P C Rooney and 4 more

Abstract read
In one paragraph

Article in Nature chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
  4. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Nai-Shu HsuYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.ORCID 0000-0002-3514-3234
Cong Tang *GIMM - Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal.ORCID 0000-0003-1661-6793
Raquel V Mendes *Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal.ORCID 0000-0003-2113-4318
Carlos Labão-AlmeidaGIMM - Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal.
Caio V Dos ReisThe ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge, UK.
Ana R CoelhoGIMM - Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal.
Marta C MarquesGIMM - Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal.
Mar Cabeza CabrerizoYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
Roman MisteliYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.ORCID 0000-0002-4830-0905
Timothy P C RooneyThe ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge, UK.ORCID 0000-0001-6788-5526
Marko HyvönenDepartment of Biochemistry, University of Cambridge, Cambridge, UK.ORCID 0000-0001-8683-4070
Francisco CorzanaDepartamento de Química and Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Universidad de La Rioja, Logroño, Spain.ORCID 0000-0001-5597-8127
Rita FiorChampalimaud Research, Champalimaud Foundation, Lisbon, Portugal.ORCID 0000-0001-5550-2428
Gonçalo J L BernardesYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK. gb453@cam.ac.uk.ORCID 0000-0001-6594-8917

Funding

Alzheimer's Research UK (ARUK) 1077089Alzheimer's Research UK (ARUK) ARUK-2015DDI-CAMAlzheimer's Research UK (ARUK) SC042474
6 · The paper itself

Abstract

Pharmacological activation of STING holds promise in cancer treatment. A recent trend is the development of tumour-specific or conditionally activated STING agonists for enhanced safety and efficacy. Here we explore an unconventional prodrug activation strategy for on-tumour synthesis of a potent agonist. Leveraging the unique mechanism of MSA2, a small-molecule agonist that dimerizes non-covalently before binding to STING, we showed that its analogues bearing reactive functional groups readily and selectively form covalent dimers under mild conditions and in complex environments. We identified a reacting pair that led to a thioether-linked dimer with submicromolar potency in cell-based assays. Caging one of the reactants with a self-immolative β-glucuronide moiety resulted in a two-component prodrug system that near-exclusively formed the active compounds in tumours overexpressing β-glucuronidase. These results exemplify the use of small-molecule recognition for on-site generation of active compounds from benign precursors.

Indexed as

Antineoplastic AgentsMembrane ProteinsNeoplasmsProdrugsAnimalsCell Line, TumorHumansSTING ProteinAntineoplastic AgentsMembrane ProteinsProdrugsSTING1 protein, humanSTING Protein

Identifiers

PMID40957952
PMCPMC12669040

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Registered trials

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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.