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

• Published in: Acta pharmaceutica Sinica. B Vol. 10; no. 12; pp. 2272 - 2298
• Main Authors: Ding, Chunyong, Song, Zilan, Shen, Ancheng, Chen, Tingting, Zhang, Ao
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-12-2020; Elsevier
• Subjects: Anti-tumor; cGAS; Immunotherapy; Review; Small molecule modulators; STING; TBK1; CDA; CXCL; CTT; GTP; Anti-tumor; CDG; CDN; ULD; MLK; ABZI; LBD; NF-κB; BNBC; QC; SDD; TBK1; Immunotherapy; CMA; ENPP1; MG; MDCK; MI; PDK1; AMP; IO; ACMA; EM; PROTACs; GMP; DMXAA; ER; i.t; IRF3; HCQ; MinEC5; PD-1; dsDNA; cAIMP; FDA; CBD; DC50; SAR; HTS; PRRs; FP; Ntase; PDE; DCs; cGAS; PD-L1; KD; CTLA-4; TNFRSF; VHL; ISG; THIQCs; FAA; IKK; PPi; PBMCs; ICI; CTD; STAT; Small molecule modulators; cGAMP; STING; ITC; DSDP; ATP; CDG, cyclic diguanosine monophosphate (c-di-GMP); MDCK, Madin–Darby canine kidney; MI, maximum induction; ENPP1, ecto-nucleotide pyrophosphatase/phosphodiesterase; HCQ, hydrochloroquine; ISG, interferon stimulated gene; DC50, concentration for 50% degradation; i.t., intratumoral; CTT, C-terminal tail; MG, Mangostin; KD, kinase domain; PRRs, pattern recognition receptors; SAR, structure–activity relationship; GMP, guanosine monophosphate; GTP, guanosine triphosphate; BNBC, 6-bromo-N-(naphthalen-1-yl)benzo[d][1,3]dioxole-5-carboxamide; FDA, U.S. Food and Drug Administration; CDA, cyclic diadenosine monophosphate (c-di-AMP); FAA, flavone-8-acetic acid; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; LBD, ligand-binding domain; THIQCs, tetrahydroisoquinolone acetic acids; ABZI, amidobenzimidazole; CTD, C-terminal domain; MinEC5×, minimum effective concentration for inducing 5-fold luciferase activity; PROTACs, proteolysis targeting chimeras; PBMCs, peripheral-blood mononuclear cells; FP, fluorescence polarization; MLK, mixed lineage kinase; CMA, 10-carboxymethyl-9-acridanone; PDK1, 3-phosphoinositide-dependent protein kinase 1; DSDP, dispiro diketopiperzine; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; CDN, cyclic dinucleotide; DCs, dendritic cells; IKK, IκB kinase; ITC, isothermal titration calorimetry; TNFRSF, tumor necrosis factor receptor superfamily; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; STING, stimulator of interferon genes; CBD, cyclic dinucleotide-binding domain; dsDNA, double-stranded DNA; ICI, immune checkpoint inhibitor; ATP, adenosine triphosphate; ULD, ubiquitin-like domain; cAIMP, cyclic adenosine-inosine monophosphate; QC, quinacrine; PD-1, programmed death receptor 1; CXCL, chemokine (C-X-C motif) ligand; SDD, scaffold and dimerization domain; VHL, von Hippel–Lindau; IRF3, interferon regulatory factor 3; STAT, signal transducer and activator of transcription; AMP, adenosine monophosphate; HTS, high throughput screening; PDE, phosphodiesterases; PPi, pyrophosphoric acid; PD-L1, programmed death ligand 1; NF-κB, nuclear factor-κB; EM, cryo-electron microscopy; IO, immune-oncology; ACMA, 9-amino-6-chloro-2-methoxyacridine; Ntase, nucleotidyl transferase; CTLA-4, cytotoxic T lymphocyte associated protein 4; ER, endoplasmic reticulum; TBK1, TANK-binding kinase 1
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2020.03.001

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.
The cGAS‒STING‒TBK1 axis is appreciated as the major signaling pathway in innate immune response, which is closely linked to multiple diseases. This review summarizes the latest progress on the development of small molecule modulators targeting the cGAS‒STING‒TBK1 signaling pathway and their clinical use as a new immune stimulatory therapy. [Display omitted]