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ID: ALA3124838
Journal: Bioorg Med Chem Lett
Title: Discovery of 6-aryl-azabenzimidazoles that inhibit the TBK1/IKK-ε kinases.
Authors: Johannes JW, Chuaqui C, Cowen S, Devereaux E, Gingipalli L, Molina A, Wang T, Whitston D, Wu X, Zhang HJ, Zinda M.
Abstract: The discovery and optimization of a series of 6-aryl-azabenzimidazole inhibitors of TBK1 and IKK-ε is described. Various internal azabenzimidazole leads and reported TBK1/IKK-ε inhibitors were docked into a TBK1 homology model. The resulting overlays inspired a focused screen of 6-substituted azabenzimidazoles against TBK1/IKK-ε. This screen resulted in initial hit compound 3. The TBK1/IKK-ε 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-ε as an oncology target.
CiteXplore: 24462666