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Merck

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

ACS medicinal chemistry letters (2019-05-18)
Douglas W Thomson, Daniel Poeckel, Nico Zinn, Christina Rau, Katrin Strohmer, Anne J Wagner, Alan P Graves, Jessica Perrin, Marcus Bantscheff, Birgit Duempelfeld, Viera Kasparcova, Joshi M Ramanjulu, G Scott Pesiridis, Marcel Muelbaier, Giovanna Bergamini
PMID31097999
ABSTRACT

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.