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

      review-article
      a , b , c , b , c , b , c , b , c , a , b , c ,
      Acta Pharmaceutica Sinica. B
      Elsevier
      Immunotherapy, Anti-tumor, cGAS, STING, TBK1, Small molecule modulators, ABZI, amidobenzimidazole, ACMA, 9-amino-6-chloro-2-methoxyacridine, AMP, adenosine monophosphate, ATP, adenosine triphosphate, BNBC, 6-bromo-N-(naphthalen-1-yl)benzo[d][1,3]dioxole-5-carboxamide, cAIMP, cyclic adenosine-inosine monophosphate, CBD, cyclic dinucleotide-binding domain, CDA, cyclic diadenosine monophosphate (c-di-AMP), CDG, cyclic diguanosine monophosphate (c-di-GMP), CDN, cyclic dinucleotide, CTLA-4, cytotoxic T lymphocyte associated protein 4, CXCL, chemokine (C-X-C motif) ligand, cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase, cGAMP, cyclic guanosine monophosphate-adenosine monophosphate, CMA, 10-carboxymethyl-9-acridanone, CTD, C-terminal domain, CTT, C-terminal tail, DC50, concentration for 50% degradation, DCs, dendritic cells, DSDP, dispiro diketopiperzine, dsDNA, double-stranded DNA, DMXAA, 5,6-dimethylxanthenone-4-acetic acid, ENPP1, ecto-nucleotide pyrophosphatase/phosphodiesterase, EM, cryo-electron microscopy, 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, i.t., intratumoral, ITC, isothermal titration calorimetry, ISG, interferon stimulated gene, KD, kinase domain, LBD, ligand-binding domain, MDCK, Madin–Darby canine kidney, MG, Mangostin, MI, maximum induction, MinEC5×, minimum effective concentration for inducing 5-fold luciferase activity, MLK, mixed lineage kinase, 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, stimulator of interferon genes, TBK1, TANK-binding kinase 1, THIQCs, tetrahydroisoquinolone acetic acids, TNFRSF, tumor necrosis factor receptor superfamily, ULD, ubiquitin-like domain, VHL, von Hippel–Lindau

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          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.

          Graphical abstract

          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.

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            The Immune Landscape of Cancer

            We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.
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              Immunotherapy is proving to be an effective therapeutic approach in a variety of cancers. But despite the clinical success of antibodies against the immune regulators CTLA4 and PD-L1/PD-1, only a subset of people exhibit durable responses, suggesting that a broader view of cancer immunity is
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                Author and article information

                Contributors
                Journal
                Acta Pharm Sin B
                Acta Pharm Sin B
                Acta Pharmaceutica Sinica. B
                Elsevier
                2211-3835
                2211-3843
                13 March 2020
                December 2020
                13 March 2020
                : 10
                : 12
                : 2272-2298
                Affiliations
                [a ]Research Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery (RLMCBFDD), School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
                [b ]CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
                [c ]University of Chinese Academy of Sciences, Beijing 100049, China
                Author notes
                []Corresponding author. Tel./fax: +86 21 50806035. aozhang@ 123456simm.ac.cn
                Article
                S2211-3835(19)31694-6
                10.1016/j.apsb.2020.03.001
                7745059
                33354501
                e5baf3dd-781f-4989-9b76-2b682748f6da
                © 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 4 December 2019
                : 20 February 2020
                : 28 February 2020
                Categories
                Review

                immunotherapy,anti-tumor,cgas,sting,tbk1,small molecule modulators,abzi, amidobenzimidazole,acma, 9-amino-6-chloro-2-methoxyacridine,amp, adenosine monophosphate,atp, adenosine triphosphate,bnbc, 6-bromo-n-(naphthalen-1-yl)benzo[d][1,3]dioxole-5-carboxamide,caimp, cyclic adenosine-inosine monophosphate,cbd, cyclic dinucleotide-binding domain,cda, cyclic diadenosine monophosphate (c-di-amp),cdg, cyclic diguanosine monophosphate (c-di-gmp),cdn, cyclic dinucleotide,ctla-4, cytotoxic t lymphocyte associated protein 4,cxcl, chemokine (c-x-c motif) ligand,cgas, cyclic guanosine monophosphate-adenosine monophosphate synthase,cgamp, cyclic guanosine monophosphate-adenosine monophosphate,cma, 10-carboxymethyl-9-acridanone,ctd, c-terminal domain,ctt, c-terminal tail,dc50, concentration for 50% degradation,dcs, dendritic cells,dsdp, dispiro diketopiperzine,dsdna, double-stranded dna,dmxaa, 5,6-dimethylxanthenone-4-acetic acid,enpp1, ecto-nucleotide pyrophosphatase/phosphodiesterase,em, cryo-electron microscopy,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,i.t., intratumoral,itc, isothermal titration calorimetry,isg, interferon stimulated gene,kd, kinase domain,lbd, ligand-binding domain,mdck, madin–darby canine kidney,mg, mangostin,mi, maximum induction,minec5×, minimum effective concentration for inducing 5-fold luciferase activity,mlk, mixed lineage kinase,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, stimulator of interferon genes,tbk1, tank-binding kinase 1,thiqcs, tetrahydroisoquinolone acetic acids,tnfrsf, tumor necrosis factor receptor superfamily,uld, ubiquitin-like domain,vhl, von hippel–lindau
                immunotherapy, anti-tumor, cgas, sting, tbk1, small molecule modulators, abzi, amidobenzimidazole, acma, 9-amino-6-chloro-2-methoxyacridine, amp, adenosine monophosphate, atp, adenosine triphosphate, bnbc, 6-bromo-n-(naphthalen-1-yl)benzo[d][1,3]dioxole-5-carboxamide, caimp, cyclic adenosine-inosine monophosphate, cbd, cyclic dinucleotide-binding domain, cda, cyclic diadenosine monophosphate (c-di-amp), cdg, cyclic diguanosine monophosphate (c-di-gmp), cdn, cyclic dinucleotide, ctla-4, cytotoxic t lymphocyte associated protein 4, cxcl, chemokine (c-x-c motif) ligand, cgas, cyclic guanosine monophosphate-adenosine monophosphate synthase, cgamp, cyclic guanosine monophosphate-adenosine monophosphate, cma, 10-carboxymethyl-9-acridanone, ctd, c-terminal domain, ctt, c-terminal tail, dc50, concentration for 50% degradation, dcs, dendritic cells, dsdp, dispiro diketopiperzine, dsdna, double-stranded dna, dmxaa, 5,6-dimethylxanthenone-4-acetic acid, enpp1, ecto-nucleotide pyrophosphatase/phosphodiesterase, em, cryo-electron microscopy, 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, i.t., intratumoral, itc, isothermal titration calorimetry, isg, interferon stimulated gene, kd, kinase domain, lbd, ligand-binding domain, mdck, madin–darby canine kidney, mg, mangostin, mi, maximum induction, minec5×, minimum effective concentration for inducing 5-fold luciferase activity, mlk, mixed lineage kinase, 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, stimulator of interferon genes, tbk1, tank-binding kinase 1, thiqcs, tetrahydroisoquinolone acetic acids, tnfrsf, tumor necrosis factor receptor superfamily, uld, ubiquitin-like domain, vhl, von hippel–lindau

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