Synthesis and SAR studies of imidazo-[1,2-a]-pyrazine Aurora kinase inhibitors with improved off-target kinase selectivity

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Abstract

The structure–activity relationships of new Aurora A/B kinase inhibitors derived from the previously identified kinase inhibitor 12 are described. Introduction of acetic acid amides onto the pyrazole of compound 12 was postulated to influence Aurora A/B selectivity and improve the profile against off-target kinases. The SAR of the acetic acid amides was explored and the effect of substitution on enzyme inhibition as well as mechanism-based cell activity was studied. Additionally, several of the more potent inhibitors were screened for their off-target kinase selectivity.

Graphical abstract

Previously reported Aurora A/B inhibitor 12 was optimized to provide selectivity against a panel of off-target kinases while retaining Aurora A/B potency and good cellular activity.

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Acknowledgments

We thank Drs. John Piwinski, Neng-Yang Shih, Paul Kirschmeier, W. Robert Bishop, Paul Zavodny and Mark Sawicki for supporting this project and the collaboration. We would also like to thank Drs. Jayaram Tagat and Tao Yu for helpful discussion on the synthesis of these compounds.

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