2. Academic Validation
  3. Macromolecular Diamidobenzimidazole Conjugates Can Activate Stimulator of Interferon Genes

Macromolecular Diamidobenzimidazole Conjugates Can Activate Stimulator of Interferon Genes

  • J Am Chem Soc. 2025 Sep 24;147(38):35149-35163. doi: 10.1021/jacs.5c13195.
Karan Arora 1,  Taylor L Sheehy 2,  Jacob A Schulman 2,  Jack R Loken 3,  Zachary Lehmann 4,  Blaise R Kimmel 1,  Caitlin McAtee 4,  Vijaya Bharti 1,  Payton T Stone 1,  Alissa M Weaver 4,  Matthew Tyska 4,  Rakesh Kumar Pathak 1 5,  John T Wilson 1 2 3 6 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37212, United States.
  • 2 Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37240, United States.
  • 3 Interdisciplinary Materials Science Program, Vanderbilt University, Nashville, Tennessee 37240, United States.
  • 4 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37240, United States.
  • 5 Department of Chemical Sciences, Indian Institutes of Science Education and Research (IISER Berhampur), Berhampur, Odisha 760010, India.
  • 6 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37240, United States.
  • 7 Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt University, Nashville, Tennessee 37212, United States.
  • 8 Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 9 Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 10 Vanderbilt Ingram Cancer Center, Nashville, Tennessee 37232, United States.
PMID: 40939638 DOI: 10.1021/jacs.5c13195
Abstract

A promising class of stimulator of interferon genes (STING) agonists is the non-nucleotide, small molecule, dimeric amidobenzimidazoles (diABZI), which have recently been incorporated into polymer- and antibody-drug conjugates to improve pharmacokinetics and modulate biodistribution for disease-specific applications. These approaches have leveraged diABZI variants functionalized at the 7-position of the benzimidazole for conjugation and tunable drug release from carriers. However, since this position does not interact with STING and is exposed from the binding pocket when bound in an "open lid" configuration, we sought to evaluate the activity of macromolecular diABZI conjugates that lack stimuli-responsive release and are instead conjugated to Polymers via a stable amide linker. By synthesizing stable mPEG-diABZI conjugates and N,N-dimethylacrylamide (DMA) homopolymers from a diABZI-functionalized reversible addition-fragmentation chain-transfer (RAFT) agent, we found that these conjugates could activate STING in vitro with similar kinetics to highly potent diABZI analogues. Our data indicate that although diABZI-DMA conjugates enter cells via endocytosis, they can still colocalize with the ER, suggesting that intracellular trafficking processes can promote the delivery of endocytosed macromolecular diABZI compounds to STING. Furthermore, we demonstrated the in vivo activity of these macromolecular diABZI platforms, which inhibited tumor growth to a similar extent as small molecule variants. In conclusion, we have described new chemical strategies for the synthesis of stable macromolecular diABZI conjugates with unexpected immunostimulatory activity─findings that have potential implications for the design of polymer-diABZI conjugates and further motivate investigation of endosomal and intracellular trafficking as an alternative route for STING activation.

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