GSK8612   Click here for help

GtoPdb Ligand ID: 10343

Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: GSK8612 is a selective inhibitor of Tank-binding kinase 1 (TBK1) [2]. TBK1 is a noncanonical member of the IκB kinase (IKK) family that is involved in regulating signalling pathways in several physiological processes including innate immunity [1,3], oncogenesis, energy homeostasis, autophagy, and neuroinflammation. TBK1 is activated downstream of TLR3/TLR4 ligand engagement, via the adaptor protein TRIF. This subsequently results in IRF3 phosphorylation and culminates in IFNβ secretion from cell types including dendritic cells and macrophages. Dysregulated TBK1 activity is associated with autoimmune disorders, hence pharmacological inhibitors are considered for the treatment of (auto)inflammatory diseases.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 3
Rotatable bonds 8
Topological polar surface area 136.2
Molecular weight 519.03
XLogP 3.52
No. Lipinski's rules broken 0
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Canonical SMILES Brc1cnc(nc1NCc1ccc(cc1)S(=O)(=O)N)Nc1cn(nc1C)CC(F)(F)F
Isomeric SMILES Brc1cnc(nc1NCc1ccc(cc1)S(=O)(=O)N)Nc1cn(nc1C)CC(F)(F)F
InChI InChI=1S/C17H17BrF3N7O2S/c1-10-14(8-28(27-10)9-17(19,20)21)25-16-24-7-13(18)15(26-16)23-6-11-2-4-12(5-3-11)31(22,29)30/h2-5,7-8H,6,9H2,1H3,(H2,22,29,30)(H2,23,24,25,26)
1. Tanaka Y, Chen ZJ. (2012)
STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.
Sci Signal, 5 (214): ra20. [PMID:22394562]
2. Thomson DW, Poeckel D, Zinn N, Rau C, Strohmer K, Wagner AJ, Graves AP, Perrin J, Bantscheff M, Duempelfeld B et al.. (2019)
Discovery of GSK8612, a Highly Selective and Potent TBK1 Inhibitor.
ACS Med Chem Lett, 10 (5): 780-785. DOI: 10.1021/acsmedchemlett.9b00027 [PMID:31097999]
3. Zhan Z, Cao H, Xie X, Yang L, Zhang P, Chen Y, Fan H, Liu Z, Liu X. (2015)
Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1.
J Immunol, 195 (8): 3849-57. [PMID:26363053]