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

Acta Pharmaceutica Sinica B 2020;10(12):2272e2298 Chinese Pharmaceutical Association Institute of Materia Medica, Chinese Academy of Medical Sciences Acta Pharmaceutica Sinica B w w w. e l s ev i e r. c o m / l o c a t e / a p s b w w w. s c i e n c e d i r e c t . c o m REVIEW Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway Chunyong Dinga,b,c, Zilan Songb,c, Ancheng Shenb,c, Tingting Chenb,c, Ao Zhanga,b,c,* 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 Received 4 December 2019; received in revised form 20 February 2020; accepted 28 February 2020 KEY WORDS Immunotherapy; Anti-tumor; 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 Abbreviations: 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-carboxymethyl9-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, IkB 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, MadineDarby canine kidney; MG, Mangostin; MI, maximum induction; MinEC5
, minimum effective concentration for inducing 5-fold luciferase activity; MLK, mixed lineage kinase; NF-kB, nuclear factor-kB; 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, structureeactivity 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 HippeleLindau. *Corresponding author. Tel./fax: þ86 21 50806035. E-mail address: (Ao Zhang). Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. https://doi.org/10.1016/j.apsb.2020.03.001 2211-3835 ª 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/). Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway cGAS; STING; TBK1; Small molecule modulators 2273 clinic success as evidenced by several U.S. Food and Drug Administration (FDA)-approved antiprogrammed 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. ª 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/). 1. Introduction The human immune system, including adaptive immunity and innate immunity, plays a pivotal role for efficient host defense against foreign genetic invasions. As the first immune barrier, the innate immunity enables the body to fight against pathogen infection through a series of signaling events, including sensing, integration and transmission of non-self or foreign dangerous signals by various pattern recognition receptors (PRRs) in dendritic cells (DCs). As the host cellular proteins, PRRs can recognize pathogen-associated molecular patterns and initiate proinflammatory cytokine response and cell-death pathways1. The adaptive immunity enables the body possess specific “memory” or long-lasting immune response against the encountered antigens. The innate immune system generally responds quickly to eradicate various foreign dangerous signals, whereas the adaptive immunity is highly dependent on the innate immunity and often requires time to generate a full-blown response. Immune system has been extensively studied as a critical function during viral invasion and bacterial infection, and its significance in cancer has captured explosive attention in recent years2. Tum (...truncated)