Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist

Zang, Ruochen; Li, Xue; Zhang, Meifang; Peng, X.; Li, Xionghao; Du, Kun; Shi, Chuanqin; Liu, Yuqian; Lin, Yuxi; Han, Wenwei; Yu, Rilei; Wang, Qian; Yang, Jinbo; Wang, Xin; Jiang, Tao

doi:10.1016/j.ejmech.2023.115184

“…Recently, Jiang and colleagues have innovatively designed a category of symmetric STING agonist, compound 23, by utilizing a suitable linker (linking strategies are shown in (Figure 25) to connect two nitrofuran molecules based on the STING inhibitor C-170. [152] Researchers analyzed the covalent inhibition mechanism of STING inhibitor C-170 and found that the warhead of C-170 is the nitrofuran group. Combined with the reported literature, researchers postulated that the presence of nitrofuran group is crucial in exerting inhibitory effects.…”

Section: Nitrofuran Derivativesmentioning

confidence: 99%

Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

Xuan,

Hu

2023

ChemMedChem

2

0

View full text Add to dashboard Cite

Stimulator of interferon genes (STING) is a crucial adaptor protein in the innate immune response. STING activation triggers cytokine secretion, including type Ⅰ interferon and initiates T cell‐mediated adaptive immunity. The activated immune system converts "cold tumors" into "hot tumors" that are highly responsive to T cells by recruiting them to the tumor microenvironment, ultimately leading to potent and long‐lasting anti‐tumor effects. Unlike most immune checkpoint inhibitors, STING agonists represent a groundbreaking class of innate immune agonists that hold great potential for effectively targeting various cancer populations and are poised to become a blockbuster in tumor immunotherapy. This review will focus on the correlation between the STING signaling pathway and tumor immunity, as well as explore the impact of STING activation on other biological processes. Ultimately, we will summarize the development and optimization of STING agonists from a medicinal chemistry perspective, evaluate their potential in cancer therapy, and identify possible challenges for future advancement.

show abstract

piSTING: A Pocket‐Independent Agonist Based on Multivalency‐Driven STING Oligomerization

Zhuo,

Wang,

Zhao

et al. 2024

Angewandte Chemie

0

View full text Add to dashboard Cite

The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket‐dependent small‐molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket‐independent STING‐activating agonists (piSTINGs), which act through multivalency‐driven oligomerization to activate STING. Additionally, a piSTING‐adjuvanted vaccine elicited a significant antibody response and inhibited tumour growth in therapeutic models. Moreover, a piSTING‐based vaccine combination with aPD‐1 showed remarkable potential to enhance the effectiveness of immune checkpoint blockade (ICB) immunotherapy. In particular, piSTING can strengthen the impact of STING pathway in immunotherapy and accelerate the clinical translation of STING agonists.

show abstract

piSTING: A Pocket‐Independent Agonist Based on Multivalency‐Driven STING Oligomerization

Zhuo,

Wang,

Zhao

et al. 2024

Angew Chem Int Ed

0

View full text Add to dashboard Cite

The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket‐dependent small‐molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket‐independent STING‐activating agonists (piSTINGs), which act through multivalency‐driven oligomerization to activate STING. Additionally, a piSTING‐adjuvanted vaccine elicited a significant antibody response and inhibited tumour growth in therapeutic models. Moreover, a piSTING‐based vaccine combination with aPD‐1 showed remarkable potential to enhance the effectiveness of immune checkpoint blockade (ICB) immunotherapy. In particular, piSTING can strengthen the impact of STING pathway in immunotherapy and accelerate the clinical translation of STING agonists.

show abstract

Design and syntheses of a bimolecular STING agonist based on the covalent STING antagonist

Cited by 4 publications

References 48 publications

Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

piSTING: A Pocket‐Independent Agonist Based on Multivalency‐Driven STING Oligomerization

piSTING: A Pocket‐Independent Agonist Based on Multivalency‐Driven STING Oligomerization

Contact Info

Product

Resources

About