Tumor-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 tumor-specific or conditionally activated STING agonists for enhanced safety and efficacy. Herein, we explored an unconventional prodrug activation strategy for on-tumor synthesis of a potent agonist. Starting from the scaffold of MSA2, a non-CDN synthetic agonist that requires non-covalent dimerization via its benzo[b]thiophene core before binding to STING, we showed that its analogs bearing reactive functional groups readily and selectively formed covalent dimers under mild conditions and in complex envi- ronments. 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 tumors overexpressing 𝛽-glucuronidase. These results exemplify the use of small-molecule recognition for on-site generation of active compounds from benign precursors.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Hsu, Nai-Shu

Advisor dc:contributor.advisor

• Bernardes, Gonçalo

• STING agonist
• prodrug
• cancer immunotherapy
• 𝛽-glucuronidase
• self-immolative

Licence

• https://www.repository.cam.ac.uk/bitstreams/b2e0b32d-532c-4069-b393-9827a6faa980/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.124674

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/394978