NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation.

Graphical abstractLead optimization work on the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline series led to identification of NMS-P937. Crystal structure of NMS-P937 with PLK1 was obtained and discussed. NMS-P937 is a potent, selective and orally available PLK1 inhibitor that is presently in Phase I clinical trials.Figure optionsDownload full-size imageDownload as PowerPoint slide