Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKKε kinases.
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.
Department of Cancer Chemistry, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. tao.wang@astrazeneca.com
Tao
T
Wang
Michael A
MA
Block
Scott
S
Cowen
Audrey M
AM
Davies
Erik
E
Devereaux
Lakshmaiah
L
Gingipalli
Jeffrey
J
Johannes
Nicholas A
NA
Larsen
Qibin
Q
Su
Julie A
JA
Tucker
David
D
Whitston
Jiaquan
J
Wu
Hai-Jun
HJ
Zhang
Michael
M
Zinda
Claudio
C
Chuaqui
D064107:Aurora Kinase B; D064127:Aurora Kinases; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C031000:benzimidazole; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; D051357:Cyclin-Dependent Kinase 2