State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
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.
Eur J Med Chem. 2022 Dec 5;243:114796. doi: 10.1016/j.ejmech.2022.114796. Epub 2022 Sep 28.
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.
癌症免疫疗法是对抗癌症的有力武器。环二核苷酸（CDNs）通过激发免疫系统来对抗癌症，显示出巨大的潜力。由于细胞通透性和血清稳定性低，在临床应用中仍然需要高度有效的 CDNs。在这里，我们报道了基于 S-酰硫基烷基酯（SATE）的脱氧核糖环二核苷酸（dCDN）前药，具有三种不同类型的核苷酸间连接（3'，3'：11a；2'，3'：11b；2'，2'：11c）。细胞酯酶可以有效地将 dCDN 从 SATE-dCDN 中释放出来。与 2'，3'-cGAMP 和 ADU-S100 相比，11a 激活 STING 途径的活性更高，血清稳定性也更高。在 CT26-Luc 荷瘤动物模型中，11a 能够有效消除已建立的肿瘤，诱导 IFN-β 和其他相关炎症细胞因子的 mRNA 表达显著增加，从而表现出有效的抗肿瘤活性。因此，SATE-dCDN 前药在促进细胞渗透、提高血清稳定性和增强生物活性方面表现出了优势，这表明它们有作为多种恶性肿瘤的免疫疗法的应用潜力。
