GSK8612

GSK8612 is a highly potent ATP-competitive inhibitor of TBK1 (Kd = 10 nM in kinobeads in vitro assay), with an approx. 10-fold higher affinity for the inactive state of the protein kinase (Kd in cell extracts of approx. 20 nM in untreated Ramos cells vs. 158 nM in Calyculin A treated cells). Kinobead selectivity profiling against 285 kinases revealed that GSK8612 has a 60-fold selectivity over STK17B and 100-fold selectivity over closely related IKKepsilon. Lipid kinobeads assay showed that GSK8612 binds only one lipid kinase (PI4Kbeta) with a potency 1000-fold lower than for TBK1. GSK8621 showed submicromolar and approx 1 uM potencies in 4 different assays in live cells (inhibits IRF3 phosphorylation, IFNalpha and IFNbeta secretion). Although no crystal structures of TBK1-GSK8612 complex are available, molecular docking studies revealed that the substituted pyrazole on N2 and the benzyl-sulfonamide substructure on the N4-amine of the pyrimidine could theoretically contribute to the high affinity and selectivity for TBK1. A negative control with a 72.73% chemical similarity is available, with no detectable affinity for TBK1 in a cell-based assay (CHEMBL5072178). The good physico-chemical properties, membrane permeability and in vitro microsomal clearance suggest that GSK8612 could be further investigated in vivo, but no toxicity or in vivo pharmacokinetic data are readily available yet. Therefore, further characterisation is needed before using GSK8612 as a chemical tool in animal models of neuroinflammation, autoimmune diseases, obesity and cancer.