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oai:www.repository.cam.ac.uk:1810/3949782026-01-28T01:43:57Zcom_1810_721com_1810_256064col_1810_218856

Tumor-Specific STING Agonist Synthesis via a Two-Component Prodrug System https://doi.org/10.17863/CAM.124674 Hsu, Nai-Shu Bernardes, Gonçalo 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. University of Cambridge 2025-08-11 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/394978 https://www.repository.cam.ac.uk/bitstreams/509bfe7c-d4ef-40cc-a524-a001dfc2d9d8/download 4cada92f11230451e5a75e105f8cf0b7 https://www.repository.cam.ac.uk/bitstreams/b2e0b32d-532c-4069-b393-9827a6faa980/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved STING agonist prodrug cancer immunotherapy 𝛽-glucuronidase self-immolative