title: Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate.
abstract: 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.
authors.affiliation: 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
authors.forename: Vassilios
authors.initials: V
authors.lastname: Bavetsias
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Large
authors.forename: Chongbo
authors.initials: C
authors.lastname: Sun
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bouloc
authors.forename: Magda
authors.initials: M
authors.lastname: Kosmopoulou
authors.forename: Mizio
authors.initials: M
authors.lastname: Matteucci
authors.forename: Nicola E
authors.initials: NE
authors.lastname: Wilsher
authors.forename: Vanessa
authors.initials: V
authors.lastname: Martins
authors.forename: Jóhannes
authors.initials: J
authors.lastname: Reynisson
authors.forename: Butrus
authors.initials: B
authors.lastname: Atrash
authors.forename: Amir
authors.initials: A
authors.lastname: Faisal
authors.forename: Frederique
authors.initials: F
authors.lastname: Urban
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Alexis
authors.initials: A
authors.lastname: de Haven Brandon
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Richard
authors.initials: R
authors.lastname: Bayliss
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
authors.forename: Edward
authors.initials: E
authors.lastname: McDonald
mesh_terms: 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
chemical_list: 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