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Aurora Isoform Selectivity: Design and Synthesis of Imidazo[4,5-b]pyridine Derivatives as Highly Selective Inhibitors of Aurora-A Kinase in Cells

DOI: 10.1021/jm401115g DOI Help
PMID: 24195668 PMID Help

Authors: Richard Bayliss (University of Leicester) , Vassilios Bavetsias (The Institute of Cancer Research) , Amir Faisal (The Institute of Cancer Research) , Simon Crumpler (The Institute of Cancer Research) , Nathan Brown (The Institute of Cancer Research) , Magda Kosmopoulou (The Institute of Cancer Research) , Amar Joshi (University of Leicester) , Butrus Atrash (The Institute of Cancer Research) , Yolanda PĂ©rez-fuertes (The Institute of Cancer Research) , Jessica A. Schmitt (The Institute of Cancer Research) , Katherine J. Boxall (The Institute of Cancer Research) , Rosemary Burke (The Institute of Cancer Research) , Chongbo Sun (The Institute of Cancer Research) , Sian Avery (The Institute of Cancer Research) , Katherine Bush (The Institute of Cancer Research) , Alan Henley (The Institute of Cancer Research) , Florence I. Reynaud (The Institute of Cancer Research) , Paul Workman (The Institute of Cancer Research) , Spiros Linardopoulos (The Institute of Cancer Research) , Julian Blagg (The Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 56 (22) , PAGES 9122-9135

State: Published (Approved)
Published: November 2013
Diamond Proposal Number(s): 8359

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.

Journal Keywords: Aurora; Aurora; Catalytic; Drug; Drug; HCT116; Humans; Imidazoles; Indoles; Isoenzymes; Male; Mice; Molecular; Protein; Substrate Specificity

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF ID14-1 SSRL BL11-1 ALS Beamline 5.0.3