Design and synthesis of 2-amino-isoxazolopyridines as Polo-like kinase inhibitors

A series of 2-amino-isoxazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors. Key SAR and crystallographic data are discussed. More advanced analogues inhibit Plk1 with good enzymatic activity and modest cell-based activity. Differential selectivity among the three Plk isoforms is observed.

Graphical abstractA series of 2-amino-isoxazolopyridine analogs was identified as inhibitors of Polo-like kinase (Plk). Co-crystal structures of inhibitors with Plk demonstrate key binding motifs. Differential selectivity among the three Plk isoforms is observed.Figure optionsDownload full-size imageDownload as PowerPoint slide