2. Academic Validation
  3. S-acylthioalkyl ester (SATE)-based prodrugs of deoxyribose cyclic dinucleotides (dCDNs) as the STING agonist for antitumor immunotherapy

S-acylthioalkyl ester (SATE)-based prodrugs of deoxyribose cyclic dinucleotides (dCDNs) as the STING agonist for antitumor immunotherapy

  • Eur J Med Chem. 2022 Sep 28;243:114796. doi: 10.1016/j.ejmech.2022.114796.
Zhiqiang Xie 1,  Liqing Lu 1,  Zhenghua Wang 1,  Qinhong Luo 2,  Yuchen Yang 1,  Tian Fang 1,  Ziyi Chen 1,  Dejun Ma 1,  Junmin Quan 3,  Zhen Xi 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
  • 2 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China; Department of Pharmacy, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), The First Affiliated Hospital of Shenzhen University, Shenzhen, 518000, China.
  • 3 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. Electronic address: quanjm@pku.edu.cn.
  • 4 State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China; National Pesticide Engineering Research Centre, Tianjin, 300071, China; Collaborative Innovation Centre of Chemical Science and Engineering (Tianjin), Tianjin, 300071, China. Electronic address: zhenxi@nankai.edu.cn.
PMID: 36198216 DOI: 10.1016/j.ejmech.2022.114796
Abstract

Cancer Immunotherapy is a powerful weapon in the fight against cancers. Cyclic dinucleotides (CDNs) have demonstrated the great potential by evoking the immune system to fight cancers. There are still a lot of unmet needs for highly active CDNs in clinical applications due to low cell permeation and serum stability. Here we reported S-acylthioalkyl ester (SATE)-based prodrugs of deoxyribose cyclic dinucleotides (dCDNs) with three different types of internucleotide linkages (3',3':11a; 2',3':11b; 2',2':11c). The parent dCDNs could be efficiently released from SATE-dCDNs by cellular esterases. Compared to 2',3'-cGAMP and ADU-S100, 11a exhibited much higher potency of activating STING pathway and higher serum stability. In a CT26-Luc tumor-bearing animal model, 11a showed the efficient antitumor activity in eliminating the established tumor and induced significant increase of mRNA expression of IFN-β and Other related inflammatory cytokines. Hence, SATE-dCDN prodrugs demonstrated their benefits in promoting cell penetration, improving serum stability, and thus enhancing bioactivity, suggesting their potential application as immunotherapy in a variety of malignancies.

Keywords

Antitumor immunotherapy; Deoxyribose cyclic dinucleotides; SATE-based prodrugs; STING agonist; Serum stability.

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