Tumor-Specific STING Agonist Synthesis via a Two-Component Prodrug System
type: CreativeWork
description: 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.
abstract: 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.
author: Hsu, Nai-Shu
language: eng
keywords: STING agonist, prodrug, cancer immunotherapy, 𝛽-glucuronidase, self-immolative
license: https://www.repository.cam.ac.uk/bitstreams/b2e0b32d-532c-4069-b393-9827a6faa980/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-08-11
date modified: 2026-07-22T22:24:14Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.124674