关键词： 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

来  源：   DOI：10.1016/j.apsb.2020.03.001   PDF(Sci-hub)   PDF(Pubmed)

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.
摘要：
包括嵌合抗原受体T细胞和免疫检查点抑制剂(ICI)的多种癌症免疫疗法已经被成功地开发以通过激发适应性抗肿瘤免疫来治疗各种癌症。特别是,检查点阻断方法在临床上取得了巨大的成功,美国食品和药物管理局(FDA)批准的几种抗程序性死亡受体1/配体1或抗细胞毒性T淋巴细胞相关蛋白4抗体证明了这一点.然而,由于肿瘤免疫原性差,大多数癌症对这些ICI的临床应答率低.的确,环磷酸鸟苷-磷酸腺苷合成酶-干扰素基因刺激因子-TANK结合激酶1(cGAS-STING-TBK1)轴现在被认为是不同物种先天免疫应答中的主要信号通路.该通路的异常信号与多种疾病密切相关,包括自身炎症,病毒感染和癌症。从这个角度来看,我们对靶向cGAS-STING-TBK1信号通路的小分子调节剂的开发及其作为新的免疫刺激疗法的临床前和临床应用的最新进展进行了最新综述.同时,临床候选人的亮点，限制和挑战，以及该领域的未来方向也进行了讨论。Further,还讨论了靶向该信号轴的小分子抑制剂及其在各种适应症中的潜在治疗用途.
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