Structure-based design of imidazo[1,2- a]pyrazine derivatives as selective inhibitors of Aurora-A kinase in cells

Co-crystallisation of the imidazo[1,2- a]pyrazine derivative 15 (3-chloro- N-(4-morpholinophenyl)-6-(pyridin-3-yl)imidazo[1,2- a]pyrazin-8-amine) with Aurora-A provided an insight into the interactions of this class of compound with Aurora kinases. This led to the design and synthesis of potent Auro...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-10, Vol.20 (20), p.5988-5993
Hauptverfasser:	Bouloc, Nathalie, Large, Jonathan M., Kosmopoulou, Magda, Sun, Chongbo, Faisal, Amir, Matteucci, Mizio, Reynisson, Jóhannes, Brown, Nathan, Atrash, Butrus, Blagg, Julian, McDonald, Edward, Linardopoulos, Spiros, Bayliss, Richard, Bavetsias, Vassilios
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Aurora Kinases Aurora-A Biological and medical sciences Cell Line, Tumor Crystallography, X-Ray General aspects Humans Kinases Medical sciences Models, Molecular Neoplasms - drug therapy Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - chemistry Protein Serine-Threonine Kinases - metabolism Pyrazines - chemical synthesis Pyrazines - chemistry Pyrazines - pharmacology Selectivity Structure-Activity Relationship
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Zusammenfassung:	Co-crystallisation of the imidazo[1,2- a]pyrazine derivative 15 (3-chloro- N-(4-morpholinophenyl)-6-(pyridin-3-yl)imidazo[1,2- a]pyrazin-8-amine) with Aurora-A provided an insight into the interactions of this class of compound with Aurora kinases. This led to the design and synthesis of potent Aurora-A inhibitors demonstrating up to 70-fold selectivity in cell-based Aurora kinase pharmacodynamic biomarker assays.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.08.091