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

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.

ABZI, amidobenzimidazole; ACMA, 9-amino-6-chloro-2-methoxyacridine; AMP, adenosine monophosphate; ATP, adenosine triphosphate; Anti-tumor; BNBC, 6-bromo-N-(naphthalen-1-yl)benzo[d][1,3]dioxole-5-carboxamide; CBD, cyclic dinucleotide-binding domain; CDA, cyclic diadenosine monophosphate (c-di-AMP); CDG, cyclic diguanosine monophosphate (c-di-GMP); CDN, cyclic dinucleotide; CMA, 10-carboxymethyl-9-acridanone; CTD, C-terminal domain; CTLA-4, cytotoxic T lymphocyte associated protein 4; CTT, C-terminal tail; CXCL, chemokine (C-X-C motif) ligand; DC50, concentration for 50% degradation; DCs, dendritic cells; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; DSDP, dispiro diketopiperzine; EM, cryo-electron microscopy; ENPP1, ecto-nucleotide pyrophosphatase/phosphodiesterase; ER, endoplasmic reticulum; FAA, flavone-8-acetic acid; FDA, U.S. Food and Drug Administration; FP, fluorescence polarization; GMP, guanosine monophosphate; GTP, guanosine triphosphate; HCQ, hydrochloroquine; HTS, high throughput screening; ICI, immune checkpoint inhibitor; IKK, IκB kinase; IO, immune-oncology; IRF3, interferon regulatory factor 3; ISG, interferon stimulated gene; ITC, isothermal titration calorimetry; Immunotherapy; KD, kinase domain; LBD, ligand-binding domain; MDCK, Madin–Darby canine kidney; MG, Mangostin; MI, maximum induction; MLK, mixed lineage kinase; MinEC5×, minimum effective concentration for inducing 5-fold luciferase activity; NF-κB, nuclear factor-κB; Ntase, nucleotidyl transferase; PBMCs, peripheral-blood mononuclear cells; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; PDE, phosphodiesterases; PDK1, 3-phosphoinositide-dependent protein kinase 1; PPi, pyrophosphoric acid; PROTACs, proteolysis targeting chimeras; PRRs, pattern recognition receptors; QC, quinacrine; SAR, structure–activity relationship; SDD, scaffold and dimerization domain; STAT, signal transducer and activator of transcription; STING; STING, stimulator of interferon genes; Small molecule modulators; TBK1; TBK1, TANK-binding kinase 1; THIQCs, tetrahydroisoquinolone acetic acids; TNFRSF, tumor necrosis factor receptor superfamily; ULD, ubiquitin-like domain; VHL, von Hippel–Lindau; cAIMP, cyclic adenosine-inosine monophosphate; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; cGAS; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; dsDNA, double-stranded DNA; i.t., intratumoral.