title: Aurora isoform selectivity: design and synthesis of imidazo[4,5-b]pyridine derivatives as highly selective inhibitors of Aurora-A kinase in cells.
abstract: Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand-Aurora protein interactions formed the basis of a design principle for imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 40f compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , London SM2 5NG, United Kingdom.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Bavetsias
authors.forename: Amir
authors.initials: A
authors.lastname: Faisal
authors.forename: Simon
authors.initials: S
authors.lastname: Crumpler
authors.forename: Nathan
authors.initials: N
authors.lastname: Brown
authors.forename: Magda
authors.initials: M
authors.lastname: Kosmopoulou
authors.forename: Amar
authors.initials: A
authors.lastname: Joshi
authors.forename: Butrus
authors.initials: B
authors.lastname: Atrash
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Pérez-Fuertes
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Schmitt
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Boxall
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burke
authors.forename: Chongbo
authors.initials: C
authors.lastname: Sun
authors.forename: Sian
authors.initials: S
authors.lastname: Avery
authors.forename: Katherine
authors.initials: K
authors.lastname: Bush
authors.forename: Alan
authors.initials: A
authors.lastname: Henley
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Richard
authors.initials: R
authors.lastname: Bayliss
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D015195:Drug Design; D004355:Drug Stability; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: C023422:7-azaindole dimer; D007093:Imidazoles; D007211:Indoles; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D064096:Aurora Kinase A; D064107:Aurora Kinase B