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Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors. 2010
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
Cyclacel Ltd., 1 James Lindsay Place, Dundee DD1 5JJ, Scotland, UK.
Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K(i) values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in cancer patients.
Related Publications
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
October 2012,
Acta crystallographica. Section E, Structure reports online,
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
September 2016,
ACS medicinal chemistry letters,
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
June 2012,
Acta crystallographica. Section E, Structure reports online,
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
December 2011,
Acta crystallographica. Section E, Structure reports online,
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
September 2014,
European journal of medicinal chemistry,
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
November 2013,
Acta crystallographica. Section E, Structure reports online,
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
December 2012,
Acta crystallographica. Section E, Structure reports online,
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
September 2017,
Future medicinal chemistry,
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
March 2006,
Bioorganic & medicinal chemistry letters,
Shudong Wang, and
Carol A Midgley, and
Frederic Scaërou, and
Joanna B Grabarek, and
Gary Griffiths, and
Wayne Jackson, and
George Kontopidis, and
Steven J McClue, and
Campbell McInnes, and
Christopher Meades, and
Mokdad Mezna, and
Andy Plater, and
Iain Stuart, and
Mark P Thomas, and
Gavin Wood, and
Rosemary G Clarke, and
David G Blake, and
Daniella I Zheleva, and
David P Lane, and
Robert C Jackson, and
David M Glover, and
Peter M Fischer
October 2011,
Acta crystallographica. Section E, Structure reports online,
