nms-p937 and Neoplasms

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.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Proliferation; Clinical Trials, Phase I as Topic; Inhibitory Concentration 50; Mice; Mice, Nude; Molecular Structure; Neoplasms; Polo-Like Kinase 1; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pyrazoles; Quinazolines; Structure-Activity Relationship; Xenograft Model Antitumor Assays