2. Academic Validation
  3. Discovery of 6-aryl-azabenzimidazoles that inhibit the TBK1/IKK-ε kinases

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

  • Bioorg Med Chem Lett. 2014 Feb 15;24(4):1138-43. doi: 10.1016/j.bmcl.2013.12.123.
Jeffrey W Johannes 1,  Claudio Chuaqui 2,  Scott Cowen 3,  Erik Devereaux 4,  Lakshmaiah Gingipalli 2,  Audrey Molina 5,  Tao Wang 6,  David Whitston 4,  Xiaoyun Wu 7,  Hai-Jun Zhang 8,  Michael Zinda 4
Affiliations

Affiliations

  • 1 Department of Cancer Chemistry, Oncology IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: [email protected].
  • 2 Department of Cancer Chemistry, Oncology IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
  • 3 Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
  • 4 Department of Cancer Bioscience, Oncology IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
  • 5 Acetylon Pharmaceuticals, Inc., Seaport Center, 70 Fargo Street, Suite 205, Boston, MA 02210, United States.
  • 6 Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
  • 7 Department of Infection Chemistry, Infection IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
  • 8 Biortus Biosciences, Building A5, 6 Dongsheng West Road, Jiangyin, Jiangsu Province 214437, China.
PMID: 24462666 DOI: 10.1016/j.bmcl.2013.12.123
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

Azabenzimidazole; IKK-ε; Kinase inhibitor; TBK1.

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