Discovery of 6-aryl-azabenzimidazoles that inhibit the TBK1/IKK-ε kinases.
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.
Department of Cancer Chemistry, Oncology IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: Jeffrey.Johannes@astrazeneca.com.
Jeffrey W
JW
Johannes
Department of Cancer Chemistry, Oncology IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Claudio
C
Chuaqui
Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Scott
S
Cowen
Department of Cancer Bioscience, Oncology IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Erik
E
Devereaux
Department of Cancer Chemistry, Oncology IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Lakshmaiah
L
Gingipalli
Acetylon Pharmaceuticals, Inc., Seaport Center, 70 Fargo Street, Suite 205, Boston, MA 02210, United States.
Audrey
A
Molina
Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States.
Tao
T
Wang
Department of Cancer Bioscience, Oncology IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
David
D
Whitston
Department of Infection Chemistry, Infection IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Xiaoyun
X
Wu
Biortus Biosciences, Building A5, 6 Dongsheng West Road, Jiangyin, Jiangsu Province 214437, China.
Hai-Jun
HJ
Zhang
Department of Cancer Bioscience, Oncology IMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Michael
M
Zinda
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase
Azabenzimidazole; IKK-ε; Kinase inhibitor; TBK1