Description
GSK8612 (2361659-62-1) is a highly selective and potent (avg. pIC50 = 6.8 versus recombinant TBK1) inhibitor of Tank-binding Kinase-1 (TBK1) with higher affinity for unactivated TBK1. It inhibited phosphorylation of IRF3 (pIC50 = 6.0), inhibited the release of IFNa from human PBMC’s (pIC50 = 6.1), and inhibited IFNb secretion from THP-1 cells (pIC50 = 5.8 dsDNA virus, 6.3 cGAMP stilmulated cells).
Uses
GSK 8612 is a highly selective TBK1 Inhibitor involved in regulating signaling pathways in immune responses.
Biological Activity
GSK8612 is a highly potent and selective inhibitor for TBK1 (Tank-binding Kinase-1) with pKd of 8.0. Within 10-fold affinity with respect to TBK1, no off-targets of GSK8612 could be identified.
in vitro
In cellular assays, this small molecule inhibits 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 is able to inhibit secretion of interferon beta (IFNβ) in response to dsDNA and cGAMP, the natural ligand for STING. GSK8612 has lower affinity for phosphorylated TBK1. GSK8612 inhibits recombinant TBK1 with an average pIC50 of 6.8 in a biochemical functional assay. The actual selectivity of GSK8612 for TBK1 in the cells will depend on the activation state of TBK1.
in vivo
GSK8612 is highly protein bound in mouse, rat and human blood.
References
[1] DOUGLASW. THOMSON. Discovery of GSK8612, a Highly Selective and Potent TBK1 Inhibitor[J]. ACS Medicinal Chemistry Letters, 2019, 10 5: 780-785. DOI:
10.1021/acsmedchemlett.9b00027
