Discovery of GSK8612, a Highly Selective and Potent TBK1 Inhibitor.

The serine/threonine protein kinase TBK1 (Tank-binding Kinase-1) is a noncanonical member of the IkB kinase (IKK) family. This kinase regulates signaling pathways in innate immunity, oncogenesis, energy homeostasis, autophagy, and neuroinflammation. Herein, we report the discovery and characterization of a novel potent and highly selective TBK1 inhibitor, GSK8612. In cellular assays, this small molecule inhibited toll-like receptor (TLR)3-induced interferon regulatory factor (IRF)3 phosphorylation in Ramos cells and type I interferon (IFN) secretion in primary human mononuclear cells. In THP1 cells, GSK8612 was able to inhibit secretion of interferon beta (IFNβ) in response to dsDNA and cGAMP, the natural ligand for STING. GSK8612 is a TBK1 small molecule inhibitor displaying an excellent selectivity profile and therefore represents an ideal probe to further dissect the biology of TBK1 in models of immunity, neuroinflammation, obesity, or cancer.

• Publication year

  2019

• Venue

  ACS Medicinal Chemistry Letters

• Publication date

  2019-03-11

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/ACSMEDCHEMLETT.9B00027PMID 31097999PMCID PMC6512007
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Impact of Mass Spectrometry-Based Technologies and Strategies on Chemoproteomics as a Tool for Drug Discovery.

  2018cited by this paper
• Type I interferon in rheumatic diseases

  2018cited by this paper
• Mycobacterium tuberculosis Transfer RNA Induces IL-12p70 via Synergistic Activation of Pattern Recognition Receptors within a Cell Network

  2018cited by this paper
• TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue.

  2018cited by this paper
• TANK-Binding Kinase 1-Dependent Responses in Health and Autoimmunity

  2018cited by this paper
• Kinase inhibitors: the road ahead

  2018cited by this paper
• Discovery of a Highly Selective Tankyrase Inhibitor Displaying Growth Inhibition Effects against a Diverse Range of Tumor Derived Cell Lines.

  2017cited by this paper
• Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1.

  2017cited by this paper
• Assessment of TANK-binding kinase 1 as a therapeutic target in cancer

  2017cited by this paper
• Human TBK 1 : A Gatekeeper of Neuroinflammation 1

  2016cited by this paper
• Human TBK1: A Gatekeeper of Neuroinflammation.

  2016cited by this paper
• Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing

  2016cited by this paper
• Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies.

  2016cited by this paper
• Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

  2016cited by this paper
• CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model.

  2016cited by this paper
• TRIF‐dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target

  2016cited by this paper
• Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes.

  2016cited by this paper
• The promise and peril of chemical probes.

  2015cited by this paper
• TBK1 inhibitors: a review of patent literature (2011 – 2014)

  2015cited by this paper
• Positive feedback regulation of type I interferon by the interferon‐stimulated gene STING

  2015cited by this paper
• Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1

  2015cited by this paper
• Crystal structure and mechanism of activation of TANK-binding kinase 1.

  2013cited by this paper
• Kinase drug discovery--what's next in the field?

  2013cited by this paper
• An inhibitor of the protein kinases TBK1/IKKε improves obesity-related metabolic dysfunctions

  2013cited by this paper
• TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling

  2012cited by this paper
• STING Specifies IRF3 Phosphorylation by TBK1 in the Cytosolic DNA Signaling Pathway

  2012cited by this paper
• The Pivotal Role of TBK1 in Inflammatory Responses Mediated by Macrophages

  2012cited by this paper
• A selective inhibitor reveals PI3Kγ dependence of T(H)17 cell differentiation.

  2012cited by this paper
• Novel cross-talk within the IKK family controls innate immunity.

  2011cited by this paper
• Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity

  2011cited by this paper
• The TRAF-associated protein TANK facilitates cross-talk within the IκB kinase family during Toll-like receptor signaling

  2011cited by this paper
• The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

  2010cited by this paper
• Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS‐induced lethality

  2010cited by this paper
• TLR4 Ligands Induce IFN-α Production by Mouse Conventional Dendritic Cells and Human Monocytes after IFN-β Priming1

  2009cited by this paper
• Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant

  2009cited by this paper
• Use of the Pharmacological Inhibitor BX795 to Study the Regulation and Physiological Roles of TBK1 and IκB Kinase ϵ

  2009cited by this paper
• The selectivity of protein kinase inhibitors: a further update.

  2007cited by this paper
• Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors

  2007cited by this paper
• IKKε and TBK1 are essential components of the IRF3 signaling pathway

  2003cited by this paper
• IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.

  2003cited by this paper

• Developing potent and selective TBK1 molecular glue degraders for cancer immunotherapy

  2026cites this paper
• Update on Non-Biological and RNA-Based Therapeutics in Chronic Inflammatory Diseases: Precision Medicine Through Small Molecules.

  2026cites this paper
• Endothelial TBK1 Deficiency Inhibits Endothelial-to-Mesenchymal Transition and Atherogenesis Through Suppressing PAK1/ERK1/2 Signaling.

  2026cites this paper
• Targeting the cGAS-STING-TBK1 pathway in cancer therapy.

  2026cites this paper
• Disrupted autophagy overactivates TBK1 and results in mitotic defects promoting chromosomal instability.

  2026cites this paper
• Dickkopf1 is a Novel Endogenous Ligand for priming NLRP3 Inflammasome in Macrophages via TLR4

  2025cites this paper
• Targeting the cGAS-STING Pathway to Modulate Immune Inflammation in Diabetes and Cardiovascular Complications: Mechanisms and Therapeutic Insights

  2025cites this paper
• Targeting pattern recognition receptors for cancer therapy: Mechanisms and strategies

  2025cites this paper
• diaPASEF-Powered Chemoproteomics Enables Deep Kinome Interaction Profiling.

  2025cites this paper
• cGAS activation converges with intracellular acidification to promote STING aggregation and pyroptosis in tumor models

  2025cites this paper
• Salvianolic acid A ameliorates sepsis through inhibiting inflammation via binding STING and modulating TBK1/IRF3 signaling pathway.

  2025cites this paper
• In vivo AAV9-SB-CRISPR screen identifies fatty acid elongase ELOVL5 as a pro-resolving mediator in lung inflammation

  2025cites this paper
• Targeting DNA damage in ageing: towards supercharging DNA repair

  2025cites this paper
• Discovery of TBK1Molecular Glue Degraders as a Potential Strategy for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD).

  2025cites this paper
• The cGAS-STING axis: a comprehensive review from immune defense to disease pathogenesis

  2025cites this paper
• Structure-Based Optimization of TBK1 Inhibitors.

  2025cites this paper
• TBK1 is a signaling hub in coordinating stress-adaptive mechanisms in head and neck cancer progression

  2025cites this paper
• TANK-binding kinase 1 inhibitor GSK8612 suppresses platelet function and thrombosis via the ERK/P38 signaling pathway.

  2025cites this paper
• Salvianolic acid A prevents UV-induced skin damage by inhibiting the cGAS-STING pathway.

  2024cites this paper
• Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer's disease.

  2024cites this paper
• Unveiling the physiological impact of ESCRT-dependent autophagosome closure by targeting the VPS37A ubiquitin E2 variant-like domain

  2024cites this paper
• CaMKII-dependent non-canonical RIG-I pathway promotes influenza virus propagation in the acute-phase of infection

  2024cites this paper
• diaPASEF-Powered Chemoproteomics Enables Deep Kinome Interaction Profiling

  2024cites this paper
• Discovery of novel TANK-Binding Kinase 1 (TBK1) inhibitor against pancreatic ductal adenocarcinoma.

  2024cites this paper
• TBK1 is involved in M‐CSF‐induced macrophage polarization through mediating the IRF5/IRF4 axis

  2024cites this paper
• Crosstalk and Prospects of TBK1 in Inflammation

  2024cites this paper
• KAT2A and KAT2B prevent double-stranded RNA accumulation and interferon signaling to maintain intestinal stem cell renewal

  2024cites this paper
• A human commensal-pathogenic fungus suppresses host immunity via targeting TBK1.

  2024cites this paper
• Role of TBK1 Inhibition in Targeted Therapy of Cancer.

  2024cites this paper
• MARCH1 negatively regulates TBK1-mTOR signaling pathway by ubiquitinating TBK1

  2024cites this paper
• DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation

  2024cites this paper
• IUPHAR ECR review: The cGAS-STING pathway: novel functions beyond innate immune and emerging therapeutic opportunities.

  2024cites this paper
• Agonists and Inhibitors of the cGAS-STING Pathway

  2024cites this paper
• STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.

  2024cites this paper
• Response to Bruton's tyrosine kinase inhibitors in aggressive lymphomas linked to chronic selective autophagy.

  2024cites this paper
• Microglial STING activation alleviates nerve injury-induced neuropathic pain in male but not female mice.

  2024cites this paper
• The Role of cGAS-STING Signalling in Metabolic Diseases: from Signalling Networks to Targeted Intervention

  2024cites this paper
• KAT2 paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells

  2023cites this paper
• Targeting TBK1 to overcome resistance to cancer immunotherapy

  2023cites this paper
• Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression

  2023cites this paper
• TLR4 agonist activity of Alcaligenes lipid a utilizes MyD88 and TRIF signaling pathways for efficient antigen presentation and T cell differentiation by dendritic cells.

  2023cites this paper
• STING antagonists, synthesized via Povarov-Doebner type multicomponent reaction.

  2023cites this paper
• Evaluation of intracellular signal molecules that regulate TLR4-stimulated inflammatory mediator expression in cultured rat chondrocytes.

  2023cites this paper
• DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation

  2023cites this paper
• Beyond DNA sensing: expanding the role of cGAS/STING in immunity and diseases

  2023cites this paper
• Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection

  2023cites this paper
• Progress in understanding the role of cGAS-STING pathway associated with programmed cell death in intervertebral disc degeneration

  2023cites this paper
• MD2 deficiency prevents high‐fat diet‐induced AMPK suppression and lipid accumulation through regulating TBK1 in non‐alcoholic fatty liver disease

  2022cites this paper
• Targeting TBK1 attenuates ocular inflammation in uveitis by antagonizing NF-κB signaling.

  2022cites this paper
• Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection

  2022cites this paper
• Application of deep generative model for design of Pyrrolo[2,3-d] pyrimidine derivatives as new selective TANK binding kinase 1 (TBK1) inhibitors.

  2022cites this paper
• Theme 03 - In Vitro Experimental Models

  2022cites this paper
• Complex Intracellular Mechanisms of TBK1 Kinase Activation Revealed by a Specific Small Molecule Inhibitor

  2022influential citation
• cGAS-STING activation contributes to podocyte injury in diabetic kidney disease

  2022influential citation
• The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

  2022cites this paper
• Inhibitory targeting cGAS-STING-TBK1 axis: Emerging strategies for autoimmune diseases therapy

  2022cites this paper
• Restructured membrane contacts rewire organelles for human cytomegalovirus infection

  2022cites this paper
• FACT subunit SUPT16H associates with BRD4 and contributes to silencing of interferon signaling

  2022cites this paper
• Chemical regulation of the cGAS-STING pathway.

  2022cites this paper
• Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study

  2022cites this paper
• Regulatory mechanisms of retinal ganglion cell death in normal tension glaucoma and potential therapies

  2022cites this paper
• The role of TBK1 in cancer pathogenesis and anticancer immunity

  2022cites this paper
• Therapeutic targeting of TANK-binding kinase signaling towards anticancer drug development: Challenges and opportunities.

  2022cites this paper
• TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration

  2021cites this paper
• VHL-based PROTACs as potential therapeutic agents: Recent progress and perspectives.

  2021cites this paper
• Chemical Probes for Understudied Kinases: Challenges and Opportunities.

  2021cites this paper
• NDP52 Protects Against Myocardial Infarction-Provoked Cardiac Anomalies Through Promoting Autophagosome–Lysosome Fusion via Recruiting TBK1 and RAB7

  2021cites this paper
• Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration

  2021cites this paper
• The cGAS–STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

  2021cites this paper
• A review on the role of TANK-binding kinase 1 signaling in cancer.

  2021cites this paper
• TANK-binding kinase 1 (TBK1): an emerging therapeutic target for drug discovery.

  2021cites this paper
• Strategy for Lead Identification for Understudied Kinases

  2021cites this paper
• Recent progress in small molecule TBK1 inhibitors: a patent review (2015– 2020)

  2021cites this paper
• Small molecule approaches to treat autoimmune and inflammatory diseases (Part I): kinase inhibitors.

  2021cites this paper
• TBK1 (TANK-binding kinase 1)-mediated regulation of autophagy in health and disease.

  2021cites this paper
• Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway

  2020cites this paper
• Signaling by cGAS-STING in Neurodegeneration, Neuroinflammation, and Aging.

  2020cites this paper
• Targeting TANK-binding kinase 1 (TBK1) in cancer

  2020cites this paper
• Discovery of BAY-985 a highly selective TBK1/Ikkε inhibitor.

  2019cites this paper