PUBLICATION
Photochemically controlled activation of STING by CAIX-targeting photocaged agonists to suppress tumor cell growth
- Authors
- Ding, C., Du, M., Xiong, Z., Wang, X., Li, H., He, E., Li, H., Dang, Y., Lu, Q., Li, S., Xiao, R., Xu, Z., Jing, L., Deng, L., Wang, X., Geng, M., Xie, Z., Zhang, A.
- ID
- ZDB-PUB-230609-48
- Date
- 2023
- Source
- Chemical science 14: 595659645956-5964 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 37293644 Full text @ Chem Sci
Citation
Ding, C., Du, M., Xiong, Z., Wang, X., Li, H., He, E., Li, H., Dang, Y., Lu, Q., Li, S., Xiao, R., Xu, Z., Jing, L., Deng, L., Wang, X., Geng, M., Xie, Z., Zhang, A. (2023) Photochemically controlled activation of STING by CAIX-targeting photocaged agonists to suppress tumor cell growth. Chemical science. 14:595659645956-5964.
Abstract
Controllable activation of the innate immune adapter protein - stimulator of interferon genes (STING) pathway is a critical challenge for the clinical development of STING agonists due to the potential "on-target off-tumor" toxicity caused by systematic activation of STING. Herein, we designed and synthesized a photo-caged STING agonist 2 with a tumor cell-targeting carbonic anhydrase inhibitor warhead, which could be readily uncaged by blue light to release the active STING agonist leading to remarkable activation of STING signaling. Furthermore, compound 2 was found to preferentially target tumor cells, stimulate the STING signaling in zebrafish embryo upon photo-uncaging and to induce proliferation of macrophages and upregulation of the mRNA expression of STING as well as its downstream NF-kB and cytokines, thus leading to significant suppression of tumor cell growth in a photo-dependent manner with reduced systemic toxicity. This photo-caged agonist not only provides a powerful tool to precisely trigger STING signalling, but also represents a novel controllable STING activation strategy for safer cancer immunotherapy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping