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.