Tumour-specific STING agonist synthesis via a two-component prodrug system

Area of Science:

• Immunology
• Pharmacology
• Organic Chemistry

Background:

• Stimulator of Interferon Genes (STING) agonists show promise for cancer treatment.
• Developing tumor-specific or conditionally activated STING agonists is crucial for improving safety and efficacy.
• Current strategies often face challenges in achieving targeted activation and minimizing off-tumor effects.

Purpose of the Study:

• To explore an unconventional prodrug activation strategy for on-tumor synthesis of a potent STING agonist.
• To leverage small-molecule recognition for the localized generation of active compounds from benign precursors.
• To design a two-component prodrug system for targeted STING activation in tumors.

Main Methods:

• Utilized MSA2, a small-molecule STING agonist known for non-covalent dimerization, as a basis for designing reactive analogues.
• Synthesized STING agonist analogues with reactive functional groups capable of forming covalent dimers under mild conditions.
• Developed a two-component prodrug system by caging one reactant with a self-immolative β-glucuronide moiety.
• Tested the prodrug system in cell-based assays and evaluated its activity in tumor models overexpressing β-glucuronidase.

Main Results:

• Identified a reactive pair that formed a potent thioether-linked covalent dimer with submicromolar potency in cell-based assays.
• Demonstrated that the β-glucuronide-caged prodrug system selectively generated active STING agonists within tumors overexpressing β-glucuronidase.
• Showcased the feasibility of on-site generation of active compounds from benign precursors using small-molecule recognition.

Conclusions:

• The developed two-component prodrug system enables on-tumor synthesis of potent STING agonists via covalent dimerization.
• This strategy offers enhanced safety and efficacy by ensuring localized activation of STING agonists within the tumor microenvironment.
• The findings highlight the potential of using specific molecular recognition for targeted drug activation and on-demand therapeutic synthesis.