diABZI STING agonist-1 trihydrochloride
[CAS# 2138299-34-8]

Identification

• Classification: Biochemical >> Antibody >> Immunity and inflammation
• Name: diABZI STING agonist-1 trihydrochloride
• Synonyms: 1-[(E)-4-[5-carbamoyl-2-[(2-ethyl-5-methylpyrazole-3-carbonyl)amino]-7-(3-morpholin-4-ylpropoxy)benzimidazol-1-yl]but-2-enyl]-2-[(2-ethyl-5-methylpyrazole-3-carbonyl)amino]-7-methoxybenzimidazole-5-carboxamide trihydrochloride
• Molecular Formula: C₄₂H₅₄Cl₃N₁₃O₇
• Molecular Weight: 959.32
• CAS Registry Number: 2138299-34-8
• SMILES: CCN1C(=CC(=N1)C)C(=O)NC2=NC3=C(N2C/C=C/CN4C5=C(C=C(C=C5OCCCN6CCOCC6)C(=O)N)N=C4NC(=O)C7=CC(=NN7CC)C)C(=CC(=C3)C(=O)N)OC.Cl.Cl.Cl

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

diABZI STING agonist-1 trihydrochloride is a synthetic small molecule designed to activate the stimulator of interferon genes (STING) pathway, an important component of the innate immune response. The STING pathway plays a critical role in detecting cytosolic DNA from pathogens or damaged cells and initiating type I interferon production and other pro-inflammatory cytokines, which help coordinate immune defenses against infections and tumors.

The diABZI (dimeric amidobenzimidazole) STING agonist series was developed to provide potent, selective, and drug-like small molecules capable of directly binding to and activating STING. Unlike natural cyclic dinucleotides that activate STING but have poor pharmacokinetic properties, diABZI compounds exhibit improved cell permeability, metabolic stability, and systemic exposure, making them attractive candidates for therapeutic applications.

diABZI STING agonist-1 trihydrochloride represents a key molecule within this series, characterized by a dimeric amidobenzimidazole scaffold that interacts with the STING protein to induce conformational changes necessary for downstream signaling. The trihydrochloride salt form enhances the compound’s solubility and stability, facilitating its use in biological assays and potential clinical formulations.

This compound was discovered through medicinal chemistry efforts aimed at mimicking or surpassing the immune-activating properties of endogenous STING ligands while overcoming limitations such as rapid degradation and poor cellular uptake. The design process included optimizing binding affinity, selectivity for human STING variants, and pharmacokinetic profiles suitable for systemic administration.

In preclinical studies, diABZI STING agonist-1 demonstrated robust activation of STING signaling pathways, leading to increased expression of interferon-stimulated genes and secretion of cytokines like interferon-beta. This activation promotes anti-tumor immune responses by enhancing dendritic cell maturation, T cell priming, and recruitment of immune effector cells to the tumor microenvironment.

Due to these immunostimulatory properties, diABZI STING agonist-1 is primarily investigated as an immuno-oncology agent. It has shown efficacy in various animal tumor models, both as a monotherapy and in combination with checkpoint inhibitors such as anti-PD-1 antibodies. This combination strategy aims to boost the immune system’s ability to recognize and destroy cancer cells more effectively.

Beyond cancer, activation of the STING pathway by compounds like diABZI STING agonist-1 is being explored in infectious diseases and vaccine adjuvant development. Its ability to enhance innate immune responses could improve the effectiveness of vaccines or antiviral therapies by strengthening early immune detection and response.

Safety and tolerability studies in preclinical models have indicated that diABZI STING agonist-1 is generally well-tolerated at effective doses, with manageable inflammatory side effects consistent with STING activation. Ongoing research focuses on optimizing dosing regimens and delivery methods to maximize therapeutic benefits while minimizing systemic inflammation.

Overall, diABZI STING agonist-1 trihydrochloride exemplifies the advancement of synthetic STING agonists as promising immunotherapeutic agents. Its design addresses key challenges of natural STING ligands, offering improved drug-like properties suitable for systemic administration. Continued development of this compound may expand the arsenal of immunomodulators for cancer treatment and other diseases where activation of innate immunity is beneficial.

References

2021. Structure�Activity Relationship Study of Amidobenzimidazole Analogues Leading to Potent and Systemically Administrable Stimulator of Interferon Gene (STING) Agonists. Journal of Medicinal Chemistry, 64(2).
DOI: 10.1021/acs.jmedchem.0c01900