Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKK kinases
The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKK 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/IKK. 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 IKK.
Wang, Tao,Block, Michael A.,Cowen, Scott,Davies, Audrey M.,Devereaux, Erik,Gingipalli, Lakshmaiah,Johannes, Jeffrey,Larsen, Nicholas A.,Su, Qibin,Tucker, Julie A.,Whitston, David,Wu, Jiaquan,Zhang, Hai-Jun,Zinda, Michael,Chuaqui, Claudio
p. 2063 - 2069
(2012/04/17)
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