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

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

  • Nat Chem. 2025 Sep 16. doi: 10.1038/s41557-025-01930-9.
Nai-Shu Hsu 1,  Cong Tang # 2 3,  Raquel V Mendes # 4,  Carlos Labão-Almeida 2,  Caio V Dos Reis 5 6,  Ana R Coelho 2,  Marta C Marques 2,  Mar Cabeza Cabrerizo 1 7,  Roman Misteli 1,  Timothy P C Rooney 5,  Marko Hyvönen 6,  Francisco Corzana 8,  Rita Fior 4,  Gonçalo J L Bernardes 9 10 11
Affiliations

Affiliations

  • 1 Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
  • 2 GIMM - Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal.
  • 3 Xi'an Fengcheng Hospital, Xi'an, China.
  • 4 Champalimaud Research, Champalimaud Foundation, Lisbon, Portugal.
  • 5 The ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge, UK.
  • 6 Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • 7 The Discovery Centre, Cambridge, UK.
  • 8 Departamento de Química and Instituto de Investigación en Química de la Universidad de La Rioja (IQUR), Universidad de La Rioja, Logroño, Spain.
  • 9 Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK. gb453@cam.ac.uk.
  • 10 GIMM - Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal. gb453@cam.ac.uk.
  • 11 Translational Chemical Biology Group, Spanish National Cancer Research Centre, Madrid, Spain. gb453@cam.ac.uk.
  • # Contributed equally.
PMID: 40957952 DOI: 10.1038/s41557-025-01930-9
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.

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