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Bioorg Med Chem Lett. 2012 Mar 1;22(5):2063-9. doi: 10.1016/j.bmcl.2012.01.018. Epub 2012 Jan 14.

Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKKε kinases.

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Department of Cancer Chemistry, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.


The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε.

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