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.
STING agonist, prodrug, cancer immunotherapy, 𝛽-glucuronidase, self-immolative
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