Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10587108 | Bioorganic & Medicinal Chemistry Letters | 2014 | 6 Pages |
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.
Keywords
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Jeffrey W. Johannes, Claudio Chuaqui, Scott Cowen, Erik Devereaux, Lakshmaiah Gingipalli, Audrey Molina, Tao Wang, David Whitston, Xiaoyun Wu, Hai-Jun Zhang, Michael Zinda,