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

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.

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Journal
Nature Chemistry
Published
2025-09-16
DOI
https://doi.org/10.1038/s41557-025-01930-9
Citations
2
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
1.59
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article

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

Carlos Labão‐Almeida, Marta C. Marques, Gonçalo J. L. Bernardes, Marko Hyvönen et al.
2 citations
Nature Chemistry
interferon and immune responses
1.59
article

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

Carlos Labão‐Almeida, Marta C. Marques, Gonçalo J. L. Bernardes, Marko Hyvönen, Ana R. Coelho, Cong Tang, Rita Fior, Timothy P. C. Rooney, C.V. dos Reis, Nai‐Shu Hsu, Francisco Corzana, Roman Misteli, Raquel V. Mendes, Mar Cabeza Cabrerizo
article en
2 citations

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.

Nature ChemistryVol. 17(12)
Champalimaud Foundation (PT), Universidad de La Rioja (ES), University of Cambridge (GB), Discovery Centre (CA), Spanish National Cancer Research Centre (ES), C4X Discovery (United Kingdom) (GB), First Hospital of Xi'an (CN), Instituto Gulbenkian de Ciência (PT)
Openalex Percentile: Top 15%
interferon and immune responses
1.59
DOIOpen Access PDFOpenAlex
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