Discovery of 6-aryl-azabenzimidaoles that inhibit the TBK1/IKK-ε kinases

Abstract The discovery and optimization of a series of 6-aryl-azabenzimidazole inhibitors of TBK1 and IKK-e is described. Various internal azabenzimidazole leads and reported TBK1/IKK-e inhibitors were docked into a TBK1 homology model. The resulting overlays inspired a focused screen of 6-substituted azabenzimidazoles against TBK1/IKK-e. This screen resulted in initial hit compound 3 . The TBK1/IKK-e enzyme and cell potency of this compound was further improved using structure guided drug design. Systematic exploration of the C6 aryl group led to compound 19 , a potent inhibitor of TBK1 with selectivity against cell cycle kinases CDK2 and Aurora B. Further elaboration and optimization gave compound 25 , a single digit nM inhibitor of TBK1. These compounds may serve as in vitro probes to evaluate TBK1/IKK-e as an oncology target.