Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate.
Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC(50) = 0.015 +/- 0.003 muM, Aurora-B IC(50) = 0.025 muM, Aurora-C IC(50) = 0.019 muM). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.
Bavetsias
Vassilios
V
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom. vassilios.bavetsias@icr.ac.uk
Large
Jonathan M
JM
Sun
Chongbo
C
Bouloc
Nathalie
N
Kosmopoulou
Magda
M
Matteucci
Mizio
M
Wilsher
Nicola E
NE
Martins
Vanessa
V
Reynisson
Jóhannes
J
Atrash
Butrus
B
Faisal
Amir
A
Urban
Frederique
F
Valenti
Melanie
M
de Haven Brandon
Alexis
A
Box
Gary
G
Raynaud
Florence I
FI
Workman
Paul
P
Eccles
Suzanne A
SA
Bayliss
Richard
R
Blagg
Julian
J
Linardopoulos
Spiros
S
McDonald
Edward
E
D000284:Administration, Oral; D000818:Animals; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064108:Aurora Kinase C; D064127:Aurora Kinases; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
C551619:3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo(4,5-b)pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole; D001798:Blood Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; D011725:Pyridines; C576921:AURKB protein, human; C576927:AURKC protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; C576928:Aurkc protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064108:Aurora Kinase C; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases