Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway

Abstract

Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors (ICIs) have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity. Particularly, the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S. Food and Drug Administration (FDA)-approved anti-programmed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies. However, the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity. Indeed, the cyclic guanosine monophosphate-adenosine monophosphate synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS‒STING‒TBK1) axis is now appreciated as the major signaling pathway in innate immune response across different species. Aberrant signaling of this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection and cancers. In this perspective, we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS‒STING‒TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy. Meanwhile, highlights on the clinical candidates, limitations and challenges, as well as future directions in this field are also discussed. Further, small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.

Understanding immunopathological fallout of human coronavirus infections including COVID‐19: Will they cross the path of rheumatologists?

“…Thus CQ and HCQ are effective in treatment of SARS and COVID-19 by preventing immunological injury to lungs. CQ and HCQ also inhibit the cGAS-STING pathway, thereby suppressing IFN-β secretion 68,71,72. ACE2 and transmembrane serine protease 2 (TMPRSS2) are IFN inducible proteins in humans, but not in mice.…”

Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

“…c-di-GMP, c-di-AMP and 3′3′-cGAMP have been discovered in prokaryotic cells ( Figure 3 ) [ 30 ]. STING is found intracellularly within the ER meaning STING agonists must penetrate the cell membrane to exert their effects [ 13 ]. However, natural CDNs are electronegative, hydrophilic and highly susceptible to enzymatic degradation by phospho-diesterases, primarily ENPP1 [ 36 , 37 , 59 ].…”

“…However, natural CDNs are electronegative, hydrophilic and highly susceptible to enzymatic degradation by phospho-diesterases, primarily ENPP1 [ 36 , 37 , 59 ]. These characteristics alongside their large size render them impermeable to cell membranes, lead to low drug bioavailability in tumour tissues, and narrow their therapeutic windows [ 13 ]. To address these limitations, various approaches are being taken such as the development of CDN DDS, synthetic CDNs, small molecule STING agonists, and ENPP1 inhibitors.…”

“…In March 2020, Eisai Inc. initiated a Phase Ia/Ib clinical trial of E7766 ( Section 6.8 ) (NCT04144140). Other than ADU-S100, further synthetic CDN compounds have been developed and are undergoing clinical trials [ 13 ]. The statuses of these compounds will be discussed in Section 6 .…”

“…A promising approach involves upregulation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon (IFN) genes (cGAS-STING) pathway, a major component of the innate immune system involved in antiviral and anti-tumour immunity [ 12 ]. Profound therapeutic effects of drugs targeting this pathway have been demonstrated in multiple preclinical murine tumour models and there are multiple ongoing clinical trials assessing the efficacy of STING agonists as monotherapies or in combination with ICI [ 13 ]. However, these drugs pose profound challenges for in vivo application, specifically their physiochemical properties, which render them poorly membrane permeable and prone to rapid enzymatic degradation [ 14 , 15 , 16 ].…”