Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route

作者：Štěpán Vyskočil, David Cardin, Jeffrey P. Ciavarri, Joe Conlon, Courtney Cullis, Dylan B. England, Rachel E. Gershman, Kenneth M. Gigstad, Krista Gipson, Alexandra E. Gould, Paul D. Greenspan, Robert Griffin, Nanda K. Gulavita, Sean Harrison, Zhigen Hu, Yongbo Hu, Akito Hata, Jian Huang, Shih‐Chung Huang, Dave Janowick, Matthew R. Jones, Vihren N. Kolev, Steven Langston, Hong Myung Lee, Gang Li, David Lok, Li‐Ting Ma, Doanh Mai, Jenna Malley, Atsushi Matsuda, Hirotake Mizutani, Miho Mizutani, Nina Molchanova, Elise Nunes, Sandeep Pusalkar, Christelle Renou, Scott Rowland, Yosuke Sato, Michael H. Shaw, Luhua Shen, Zhan Shi, R.J. Skene, François Soucy, Steve Stroud, He N. Xu, Tianlin Xu, Adnan O. Abu‐Yousif, Ji Zhang · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c00374 · 被引用次数：44 · 研究领域：interferon and immune responses、Viral Infections and Vectors、Immune Response and Inflammation

High Resolution Image Download MS PowerPoint Slide Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.