Design and synthesis of 2-amino-pyrazolopyridines as Polo-like kinase 1 inhibitors

A series of 2-amino-pyrazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors based on a low micromolar hit. The SAR was developed to provide compounds exhibiting low nanomolar inhibitory activity of Plk1; the phenotype of treated cells is consistent with Plk1 inhibition. A co-crystal structure of one of these compounds with zPlk1 confirms an ATP-competitive binding mode.

Graphical abstractA series of 2-amino-pyrazolopyridine analogs was identified as inhibitors of Polo-like kinase 1 (Plk1). The SAR studies led to the discovery of several compounds demonstrating Plk1 inhibition in cell based assays. Co-crystal structures of inhibitors with zPlk1 demonstrate key binding motifs.Figure optionsDownload full-size imageDownload as PowerPoint slide