Hit generation and exploration: imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases.
A hit generation and exploration approach led to the discovery of 31 (2-(4-(6-chloro-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide), a potent, novel inhibitor of Aurora-A, Aurora-B and Aurora-C kinases with IC(50) values of 0.042, 0.198 and 0.227microM, respectively. Compound 31 inhibits cell proliferation and has good microsomal stability.
Bavetsias
Vassilios
V
Department of Chemistry, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Cancer Research UK Laboratory, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK. Vassilios.Bavetsias@icr.ac.uk
Sun
Chongbo
C
Bouloc
Nathalie
N
Reynisson
Jóhannes
J
Workman
Paul
P
Linardopoulos
Spiros
S
McDonald
Edward
E
D064107:Aurora Kinase B; D064108:Aurora Kinase C; D064127:Aurora Kinases; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology
D006131:Growth Inhibitors; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011687:Purines; D011725:Pyridines; C064191:1H-imidazo(4,5-b)pyridine; C576921:AURKB protein, human; C576927:AURKC protein, human; D064107:Aurora Kinase B; D064108:Aurora Kinase C; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases