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

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• 作者：Jeffrey W. Johannes ; Claudio Chuaqui ; Scott Cowen ; Erik Devereaux ; Lakshmaiah Gingipalli ; Audrey Molina ; Tao Wang ; David Whitston ; Xiaoyun Wu ; Hai-Jun Zhang ; Michael Zinda
• 关键词：TBK1 ; IKK-蔚 ; Azabenzimidazole ; Kinase inhibitor
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 February, 2014
• 年：2014
• 卷：24
• 期：4
• 页码：1138-1143
• 全文大小：2291 K

文摘

The discovery and optimization of a series of 6-aryl-azabenzimidazole inhibitors of TBK1 and IKK-蔚 is described. Various internal azabenzimidazole leads and reported TBK1/IKK-蔚 inhibitors were docked into a TBK1 homology model. The resulting overlays inspired a focused screen of 6-substituted azabenzimidazoles against TBK1/IKK-蔚. This screen resulted in initial hit compound 3. The TBK1/IKK-蔚 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-蔚 as an oncology target.