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
  • 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. [email protected].
  • 10. GIMM - Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal. [email protected].
  • 11. Translational Chemical Biology Group, Spanish National Cancer Research Centre, Madrid, Spain. [email protected].
  • # 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.

Products